Adenine compound and use thereof

ABSTRACT

A drug for topically administration which is effective as an antiallergic agent. The drug for topically administration contains as an active ingredient an adenine compound represented by the general formula (1): 
                         
[wherein ring A represents a 6 to 10 membered, mono or bicyclic, aromatic hydrocarbon or a 5 to 10 membered, mono or bicyclic, aromatic heterocycle containing one to three heteroatoms selected among 0 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom; n is an integer of 0 to 2; m is an integer of 0 to 2; R represents halogeno, (un)substituted alkyl, etc.; X 1  represents oxygen, sulfur, NR 1  (R 1  represents hydrogen or alkyl), or a single bond; Y 1  represents a single bond, alkylene, etc.; Y 2  represents a single bond, alkylene, etc.; Z represents alkylene; and at least one of Q 1  and Q 2  represents —COOR 10  (wherein R 10  represents (un)substituted alkyl, etc.), etc.] or a pharmaceutically acceptable salt of the compound.

This application is a Continuation of the U.S. application Ser. No.10/528,343 filed Mar. 18, 2005, which is the national stage ofInternational Application PCT/JP2003/012320, filed Sep. 26, 2003, whichclaims priority under 35 USC §119(a)-(d) of Japanese Application No.2002-283428, filed Sep. 27, 2002 and of Japanese Application No.2002-301213, filed Oct. 16, 2002.

TECHNICAL FIELD

The present invention relates to a novel adenine compound which isuseful as a prophylactic or therapeutic agent for viral diseases,allergic diseases, etc.

BACKGROUND ART

Interferon is an endogenous protein which plays an important role inmammalian immune system, takes a part of nonspecific defensive mechanismin vivo and greatly participates also to specific defensive mechanism invivo. In fact, interferon has been used in the clinical field as atherapeutic agent for viral diseases, such as hepatitis B and C, etc.Low molecular weight organic compounds which induce biosynthesis of saidinterferon (interferon inducers) have been developed as an interferonpreparation in next generation. Imidazoquinoline derivatives (seeEuropean Patent Publication A 145340), adenine derivatives (see WO98/01448 and WO 99/28321), etc. are illustrated. For example, Imiquimod,an imidazoline derivative is used in the clinical field as an externalantiviral agent for genital verruca.

By the way, T cells which play the key role of the immunologicalresponse in vivo are classified into two kinds, Th1 cells and Th2 cells.In the body of patients suffering from allergic disease, cytokines suchas interleukin 4 (IL-4), interleukin 5 (IL-5), etc. are excessivelysecreted from TH2 cells and therefore, it is expected that the compoundwhich suppresses immune response of Th2 cells becomes a therapeuticagent for allergic diseases.

It is known that the above imidazoquinoline derivatives and adeninederivatives have not only the interferon inducing activity, but alsohave the activity suppressing the production of interleukin 4 (IL-4) andinterleukin 5 (IL-5). In fact it is known that these derivatives areeffective for allergic diseases on animal model.

However, there is anxiety for systemic adverse-effects due to theinterferon inducing activity such as fever, interferon-like diseaseswhen these derivatives are administered as an antiallergic agent.

DISCLOSURE OF INVENTION

The problem to be solved by the present invention is to provide atopically administrable medicament which is characterized in suppressingthe systemic adverse effect caused by interferon inducing activity.

That is, the present invention provides a novel adenine compound whichis characterized in being quickly metabolized to change a less activecompound when it is topically administered, and a topicallyadministrable medicament containing this compound as an activeingredient, which is used as the therapy for viral diseases, cancer orallergic diseases, whose systemic pharmacological activity is lessened.

The present inventors have been extensively studied in order to obtain atherapeutic and prophylactic agent for immune deficiency such asallergic diseases which shows excellent effect in the applied area anddoes not show the systemic adverse effect, when it is externally used inthe form of liniments or aerosols useful for diseases such as asthma,etc. and as a result have found that the adenine compounds of thepresent invention show surprisingly excellent effect on pathologicallymodeled animals and is characterized in being quickly metabolized in theapplied area or the body to change into a less active compound. Namely,the compounds of the present invention are reduced in the systemicallypharmacological activity and are useful as a therapeutic or prophylacticagent for viral diseases, cancer, allergic diseases, etc. The presentinvention was completed based on the above findings.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows anti-HSV activity on a compound of Example 20 against apathologic modeled-animal infected with HSV-2 in its vagina.

Compound A was spread to a vagina of a female mouse (BALB/c) to whichpreviously Depo-Provera was administered, and on next day, HSV-2 wasinfected to the vagina. Nine days later, the rate of survival or deathof mice was observed and compared.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention relates to

-   [1] A topically administrable medicament containing an adenine    compound represented by a general formula (1):

wherein

-   Ring A is a 6 to 10 membered mono or bicyclic aromatic hydrocarbon    ring or a 5 to 10 membered mono or bicyclic heteroaromatic ring    containing 1 to 3 hetero atoms selected from the group of 0 to 2    nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom,-   n is an integer selected from 0 to 2, m is an integer selected from    0 to 2,-   R is halogen atom, substituted or unsubstituted alkyl group,    substituted or unsubstituted cycloalkyl group, substituted or    unsubstituted alkoxy group, or substituted or unsubstituted amino    group, and when n is 2, R(s) may be the same or different,-   X¹ is oxygen atom, sulfur atom, NR¹ (wherein R¹ is hydrogen atom or    alkyl group) or a single bond,-   Y¹ is a single bond, alkylene which may be substituted by oxo group,    or divalent group of the formula below:

(wherein r¹ and r² are independently an integer selected from 1 to 3),

-   Y² is a single bond, alkylene optionally substituted by hydroxy    group or oxo group, oxyalkylene, cycloalkylene, oxycycloalkylene,    divalent group of a monocyclic hetero ring containing 1 or 2 hetero    atoms selected from the group consisting of 1 or 2 nitrogen atoms    wherein said nitrogen atom may be substituted, oxygen atoms and    sulfur atoms wherein said sulfur atom(s) may be oxidized by 1 to 2    oxygen atoms, or divalent group of the formula below:

(wherein A is cycloalkylene, s¹ is an integer selected from 1 to 3),

-   Z is alkylene,-   Q¹ is hydrogen atom, halogen atom, hydroxy group, alkoxy group, or a    group selected from the group consisting of Substituents illustrated    below,-   Q² is a group selected from the group consisting of Substituents    illustrated below,-   R¹⁰ or R¹¹ in Q² may be taken with R to form a 9 to 14 membered    fused bi or tricyclic ring together with the adjacent Ring A,-   when m is 0, Q¹ is a group selected from the group consisting of    Substituents illustrated below,

Substituents: —COOR¹⁰; —COSR¹⁰; —OCOOR¹⁰; —OCOR¹⁰; —CONR¹¹R¹²;—OCONR¹¹R¹²

(wherein R¹⁰ is substituted or unsubstituted alkyl group, substituted orunsubstituted cycloalkyl group, substituted or unsubstituted alkenygroup, substituted or unsubstituted cycloalkeny group, or substituted orunsubstituted alkynyl group, R¹¹ and R¹² are independently hydrogenatom, substituted or unsubstituted alkyl group, substituted orunsubstituted cycloalkyl group, substituted or unsubstituted alkenygroup, substituted or unsubstituted cycloalkeny group, or substituted orunsubstituted alkynyl group, or R¹¹ and R¹² may be taken together toform with the adjacent nitrogen atom a 5 to 7 membered heterocyclecontaining a nitrogen atom(s));and any group selected from the following formulas (3)˜(6):

(wherein M is a single bond, oxygen atom or sulfur atom, and q is aninteger selected from 1 to 3),and when m is 2, (Y²-Q²)(s) may be the same or different,or a pharmaceutically acceptable salt thereof as an active ingredient;

-   [2] The topically administrable medicament containing an adenine    compound described in the above [1], wherein in the general formula    (1), at least one of Q¹ and Q² is —COOR¹⁰, —COSR¹⁰, —OCOR¹⁰,    —OCOOR¹⁰ or —CONR¹¹R¹²;-   [3] The topically administrable medicament containing an adenine    compound described in the above [1] or [2]: wherein in the general    formula (1), the substituent(s), by which alkyl group, alkeny group    or alkynyl group in R¹⁰, R¹¹ and R¹² is substituted, are the same or    different and at least one substituent selected from the group    consisting of halogen atom, hydroxy group, substituted or    unsubstituted alkoxy group, substituted or unsubstituted amino    group, substituted or unsubstituted aryl group, and substituted or    unsubstituted heterocyclic group;-   [4] The topically administrable medicament containing an adenine    compound described in any one of the above [1] to [3]: wherein in    the general formula (1), Z is methylene and Ring A is benzene;-   [5] The topically administrable medicament containing an adenine    compound described in the above [4]: wherein in the general formula    (1), Y¹ is C₁₋₅ alkylene, Q¹ is hydrogen atom, hydroxy group or    alkoxy group, Y² is a single bond, and Q² is —COOR¹⁰;-   [6] The topically administrable medicament containing an adenine    compound described in the above [5]: wherein in the general formula    (1), Z is methylene, Ring A is benzene, R¹⁰ is alkyl group    substituted by hydroxy group, amino group, alkylamino group or    dialkylamino group, and m is 1;-   [7] The topically administrable medicament containing an adenine    compound described in the above [4]: wherein in the general formula    (1), Y¹ is C₁₋₅ alkylene, Q¹ is hydrogen atom, hydroxy group or    alkoxy group, Y² is C₁₋₃ alkylene, Q² is —COOR¹⁰, and m is 1;-   [8] The topically administrable medicament containing an adenine    compound described in the above [4]: wherein in the general formula    (1), m is 0, Y¹ is C₁₋₆ alkylene which may be substituted with oxo    group, and Q¹ is —COOR¹⁰, —COSR¹⁰, —OCOR¹⁰, —OCOOR¹⁰, —CONR¹¹R¹² or    —OCONR¹¹R¹²;-   [9] The topically administrable medicament containing an adenine    compound described in any one of the above [1] to [8]: wherein in    the general formula (1), and X¹ is oxygen atom, sulfur atom or NR¹    (wherein R¹ is hydrogen atom or alkyl group);-   [10] The topically administrable medicament containing an adenine    compound described in any one of the above [1] to [4]: wherein in    the general formula (1), m is 0, X¹ is a single bond, Y¹ is C₁₋₄    alkylene which may be substituted by oxo group, and Q¹ is —COOR¹⁰;-   [11] The topically administrable medicament containing an adenine    compound described in any one of the above [1] to [10]: wherein in    the general formula (1), the limitation is either 1) or 2) below:    1) n is 0;    2) n is 1 or 2, and R is alkyl group, alkoxy group or halogen atom;-   [12] The adenine compound or its pharmaceutically acceptable salt    described in the above [1]: wherein in the general formula (1), at    least one of Q¹ and Q² is a substituent selected from the following    formulae (3)˜(6):

(M is a single bond, oxygen atom or sulfur atom, and q is an integerselected from 1 to 3);

-   [13] The adenine compound or its pharmaceutically acceptable salt    described in the above [1]: wherein in the general formula (1), at    least one of Q¹ and Q² is —COSR¹⁰, —OCOOR¹⁰, —OCOR¹⁰ or —OCONR¹¹R¹²    (wherein, R¹⁰, R¹¹ and R¹² are the same as defined in [1]);-   [14] The adenine compound or its pharmaceutically acceptable salt    described in the above [1]: wherein in the general formula (1), Q is    —COOR²⁰ (R²⁰ is substituted or unsubstituted alkeny group or    substituted or unsubstituted alkynyl group);-   [15] The adenine compound or its pharmaceutically acceptable salt    described in the above [1]: wherein in the general formula (1), Q¹    is —CONR²¹R²² (R²¹ and R²² are independently, substituted or    unsubstituted alkeny group or substituted or unsubstituted alkynyl    group, or R²¹ and R²² are taken together to form with the adjacent    nitrogen atom a 5 to 7 membered heterocyclic ring containing a    nitrogen atom represented by the formula (2):

wherein Y³ is a single bond, methylene, oxygen atom, sulfur atom, SO,SO₂, NR¹⁴ (wherein R¹⁴ is hydrogen atom, C₁₋₄ alkyl group, C₂₋₄alkylcarbonyl group, C₂₋₄ alkoxycarbonyl group or C₁₋₄ alkylsulfonylgroup),

-   q¹ is an integer selected from 0 to 4, and-   R¹³ is hydroxy group, carboxy group, C₁₋₄ alkyl group, C₁₋₄ alkoxy    group or C₂₋₄ alkoxycarbonyl group;-   [16] The adenine compound or its pharmaceutically acceptable salt    described in the above [1]: wherein in the general formula (1), Z is    methylene, and Ring A is naphthalene;-   [17] The adenine compound or its pharmaceutically acceptable salt    described in the above [1]: wherein in the general formula (1), Z is    methylene, Ring A is a 5 to 10 membered mono or bicyclic hetero ring    containing 1 to 3 heteroatoms selected from the group consisting of    0 to 2 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom;-   [18] The adenine compound or its pharmaceutically acceptable salt    described in the above [17]: wherein in the general formula (1) in    the above [1], the heteroaromatic ring in Ring A is furan,    thiophene, or pyridine;-   [19] The adenine compound or its pharmaceutically acceptable salt    described in any one of the above described [16] to [18]: wherein in    the general formula (1) in the above [1], Q¹ is hydrogen atom,    hydroxy group or alkoxy group, Y¹ is C₁₋₅ alkylene, Q² is —COOR¹⁰    (wherein R¹⁰ is the same as defined in claim 1), and m is 1;-   [20] The adenine compound or its pharmaceutically acceptable salt    described in the above [19]: wherein in the general formula (1) in    the above [1], Y² is a single bond;-   [21] The adenine compound, its tautomer or its pharmaceutically    acceptable salt described in any one of the above described [16] to    [18]: wherein in the general formula (1) in the above [1], m is 0,    Y¹ is C₁₋₆ alkylene which may be substituted by oxo group, and Q¹ is    —COOR¹⁰, —COSR¹⁰, —OCOR¹⁰, —OCOOR¹⁰, —CONR¹¹R¹² or —OCONR¹¹R¹²    (wherein R¹⁰, R¹¹ and R¹² are the same as defined in [1]);-   [22] The adenine compound or its pharmaceutically acceptable salt    described in the above [1]: wherein in the general formula (1), Y²    is alkylene or oxyalkylene, and Q² is —COSR¹⁰ or —CONR¹¹R¹² (R¹⁰,    R¹¹, and R¹² is the same as defined in [1]);-   [23] The adenine compound or its pharmaceutically acceptable salt    described in the above [1]: wherein in the general formula (1), Y²    is divalent group of a saturated monocyclic heteroring containing    1˜2 hetero atoms selected from substituted or unsubstituted 1˜2    nitrogen atoms, oxygen atoms and sulfur atoms (said sulfur atom may    be oxidized by 1 or 2 oxygen atoms);-   [24] The adenine compound or its pharmaceutically acceptable salt    described in the above [23]: wherein divalent group of the saturated    monocyclic heteroring is piperazin-1,4-diyl;-   [25] The adenine compound or its pharmaceutically acceptable salt    described in the above [23] or [24]: wherein in the general formula    (1), Q² is —COOR¹⁰ (wherein R¹⁰ is the same as defined in [1]);-   [26] The adenine compound or its pharmaceutically acceptable salt    described in any one of the above [12] to [25], wherein in the    general formula (1), the substituent(s) by which alkyl group, alkeny    group or alkynyl group in R¹⁰, R¹¹, R¹², R²⁰, R²¹ and R²² is    substituted, are at least one substituent selected from the group    consisting of halogen atom, hydroxy group, substituted or    unsubstituted alkoxy group, substituted or unsubstituted amino    group, substituted or unsubstituted aryl group, and substituted or    unsubstituted heterocyclic group;-   [27] The adenine compound or its pharmaceutically acceptable salt    described in any one of the above [12] to [25], wherein R is    hydrogen atom, alkyl group, alkoxy group, or halogen atom;-   [28] The adenine compound or its pharmaceutically acceptable salt    described in the above [1], wherein in the general formula (1), Z is    methylene, Ring A is benzene, Q¹ is hydrogen atom, hydroxy group or    alkoxy group, Y¹ is C₁₋₅ alkylene, Y² is a single bond, Q² is    —COOR²³ (wherein R²³ is alkyl group substituted by amino group,    alkylamino group or dialkylamino group), and m is 1;-   [29] The adenine compound or its pharmaceutically acceptable salt    described in the above [1], wherein in the general formula (1), Z is    methylene, Ring A is benzene, Q¹ is hydrogen atom, hydroxy group or    alkoxy group, Y¹ is C₁₋₅ alkylene, Y² is a single bond, and Q² is    —COSR²⁴ (wherein R²⁴ is hydroxy group or alkyl group which is    substituted by substituted or unsubstituted amino group);-   [30] The adenine compound or its pharmaceutically acceptable salt    described in the above [1], wherein in the general formula (1), Z is    methylene, Ring A is benzene, Q¹ is hydrogen atom, hydroxy group or    alkoxy group, Y¹ is C₁₋₅ alkylene, Y² is a single bond, and Q² is    —CONR²⁵R²⁶ (wherein R²⁵ is hydrogen atom, alkyl group, alkeny group,    or alkynyl group, and R²⁶ is hydroxy group, or alkyl group which is    substituted by substituted or unsubstituted amino group);-   [31] The adenine compound or its pharmaceutically acceptable salt    described in any one of the above [12] to [30], wherein in the    general formula (1), X¹ is oxygen atom, sulfur atom or NR¹ (R¹ is    hydrogen atom or alkyl group);-   [32] A medicament containing the adenine compound or its    pharmaceutically acceptable salt described in any one of the above    [12] to [30] as an active ingredient;-   [33] A pharmaceutical composition containing the adenine compound or    its pharmaceutically acceptable salt described in any one of the    above [12] to [31] as an active ingredient;-   [34] An immunoregulating agent containing the adenine compound or    its pharmaceutically acceptable salt described in any one of the    above [12] to [31] as an active ingredient;-   [35] A prophylactic or therapeutic agent for viral diseases    containing the adenine compound or its pharmaceutically acceptable    salt described in any one of the above [12] to [31] as an active    ingredient;-   [36] A prophylactic or therapeutic agent for allergic diseases    containing the adenine compound or its pharmaceutically acceptable    salt described in any one of the above [12] to [31] as an active    ingredient;-   [37] A prophylactic or therapeutic agent for allergic diseases    described in [36] wherein the disease is asthma or atopic    dermatosis;-   [38] A prophylactic or therapeutic agent for cancer diseases    containing the adenine compound or its pharmaceutically acceptable    salt described in any one of the above [12] to [31] as an active    ingredient;-   [39] A topically administrable preparation containing the adenine    compound or its pharmaceutically acceptable salt described in any    one of the above [12] to [31] as an active ingredient;-   [40] The topically administrable preparation described in any one of    the above [1] to [11], wherein the preparation is a prophylactic and    therapeutic agent for viral diseases, dermal diseases or allergic    diseases;-   [41] The topically administrable preparation described in the above    [40] wherein the allergic disease is asthma;-   [42] The topically administrable preparation described in the above    [40] wherein the allergic disease is atopic dermatosis;-   [43] The topically administrable preparation described in any one of    the above [1] to [11], and [39] to [42] wherein the half-life in    serum on the compound of the general formula (1) is less than 1    hour;-   [44] The topically administrable preparation described in any one of    the above [1] to [11], and [39] to [42] wherein the half-life in    liver S9 on the compound of the general formula (1) is less than 1    hour;-   [45] The topically administrable preparation described in any one of    the above [1] to [11], and [39] to [42] wherein the interferon    concentration in serum is less than 10 IU/ml after said compound is    topically administered;-   and-   [46] The topically administrable preparation described in any one of    the above [1] to [11], and [39] to [42] wherein the preparation is    an inhalation formulation.

The mode of the present invention is described in detail below.

“Halogen” includes fluorine atom, chlorine atom, bromine atom and iodineatom, especially preferably fluorine atom and chlorine atom.

“Alkyl group” includes C₁₋₁₀ straight or branched alkyl group, such asmethyl group, ethyl group, propyl group, 1-methylethyl group, butylgroup, 2-methylpropyl group, 1-methylpropyl group, 1,1-dimethylethylgroup, pentyl group, 3-methylbutyl group, 2-methylbutyl group,2,2-dimethylpropyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group,hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentylgroup, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, heptyl group,1-methylhexyl group, 1-ethylpentyl group, octyl group, 1-methylheptylgroup, 2-ethylhexyl group, nonyl group, decyl group, etc., preferablyC₁₋₆ alkyl group, more preferably C₁₋₄ alkyl group.

Alkyl moiety in “alkylcarbonyl group”, “alkylsulfonyl group”,“alkylamino group” and “dialkylamino group” includes the same as theabove alkyl group. Two alkyl moieties in the above dialkylamino groupmay be the same or different.

“Cycloalkyl group” includes a 3 to 8 membered mono cycloalkyl group,such as cyclopropyl group, cyclobutyl group, cyclopentyl group,cycloheptyl group, cyclooctyl group, etc.

“Alkoxy group” includes C₁₋₁₀ straight or branched alkoxy group, such asmethoxy group, ethoxy group, propoxy group, 1-methylethoxy group, butoxygroup, 2-methylpropoxy group, 1-methylpropoxy group, 1,1-dimethylethoxygroup, pentoxy group, 3-methylbutoxy group, 2-methylbutoxy group,2,2-dimethylpropoxy group, 1-ethylpropoxy group, 1,1-dimethylpropoxygroup, hexyloxy group, 4-methylpentyloxy group, 3-methylpentyloxy group,2-methylpentyloxy group, 1-methylpentyloxy group, 3,3-dimethylbutoxygroup, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group,1,2-dimethylbutoxy group, heptyloxy group, 1-methylhexyloxy group,1-ethylpentyloxy group, octyloxy group, 1-methylheptyloxy group,2-ethylhexyloxy group, nonyloxy group, decyloxy group, etc., preferablyC₁₋₆ alkoxy group, more preferably C₁₋₄ alkoxy group.

Alkoxy moiety in “alkoxycarbonyl group” is the same as in the abovealkoxy group.

“Alkenyl group” includes, C₂₋₈ straight or branched alkenyl group having1 to 3 double bonds, such as ethenyl group, 1-propenyl group, 2-propenylgroup, 1-methylethenyl group, 1-butenyl group, 2-butenyl group,3-butenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenylgroup, 4-pentenyl group, 3-methyl-2-butenyl group, 1-hexenyl group,2-hexenyl group, 1-octenyl group, etc., preferably C₂₋₄ alkeny group.

“Cycloalkeny group” includes a 3 to 8 membered monocycloalkeny grouphaving 1 or 2 double bonds, such as cyclobutenyl group, cyclopentenylgroup, cyclopentadienyl group, cyclohexenyl group, cyclohexadienylgroup, cycloheptenyl group, cycloheptadienyl group, cyclooctenyl group,etc.

“Alkynyl group” includes C₂₋₈ straight or branched alkynyl group having1 or 2 triple bonds, such as ethynyl group, 1-propynyl group, 2-propynylgroup, 1-butynyl group, 2-butynyl group, 3-butynyl group,1-methyl-2-propynyl group, 1-pentynyl group, 2-pentynyl group,3-pentynyl group, 5-pentynyl group, 1-methyl-3-butynyl group, 1-hexynylgroup, 2-hexynyl group, etc., preferably C₂₋₄ alkynyl group.

“Aryl group” includes phenyl group, 1-naphthyl group or 2-naphthylgroup.

“Heterocyclic group” includes a heteroaromatic group or an aliphaticheterocyclic group.

“The heteroaromatic group” includes a 5 to 10 membered mono or bicyclicheteraromatic group containing 1 to 3 hetero atoms selected from 0 to 3nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom, such asfuryl group, thienyl group, pyrrolyl group, pyridyl group, indolylgroup, isoindolyl group, quinolyl group, isoquinolyl group, pyrazolylgroup, imidazolyl group, pyrimidinyl group, pyrazinyl group, pyridazinylgroup, thiazolyl group, oxazolyl group, etc. The binding position onsaid heteroaromatic group is not limited and said heteroaromatic groupmay be bound via an optional carbon atom or nitrogen atom thereof.

“The aliphatic heterocyclic group” includes a 5 to 8 membered monocyclicaliphatic heterocyclic group containing 1 to 3 hetero atoms selectedfrom 0 to 3 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom,such as pyrrolidinyl group, piperazinyl group, piperidinyl group,morpholinyl group, thiomorpholinyl group, 1-oxothiomorpholinyl group,1,1-dioxothiomorpholinyl group, etc. The binding position on saidaliphatic heterocyclic group is not limited and said aliphaticheterocyclic group may be bound via an optional carbon atom or nitrogenatom thereof.

“Alkylene” includes C₁₋₆ straight or branched alkylene, such as,methylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene,1-methylethylene, 2-methylethylene, 1-methyltrimethylene,2-methyltrimethylene, 2-methyltetramethylene, 3-methylpentamethylene,etc.

“Oxyalkylene” includes C₁₋₆ straight or branched oxyalkylene, such as adivalent group shown as —OCH₂—, —O(CH₂)₂—, —O(CH₂)₃—, —O(CH₂)₄—,—O(CH₂)₅—, —O(CH₂)₆—, —OCH(CH₃)—, —OCH(CH₂CH₃)—, —O—CH(CH₂CH₂CH₃)—,—OCH(CH₃)CH₂—, —OCH₂CH(CH₃)—, —OCH(CH₃)CH₂CH₂—, —OCH₂CH(CH₃)CH₂—,—OCH₂CH(CH₃)CH₂CH₂—, or —OCH₂CH₂CH(CH₃)CH₂CH₂—.

“Cycloalkylene” includes a 4 to 7 membered monocyclic cycloalkylene,such as 1,3-cyclobutandiyl, 1,3-cyclopentandiyl, 1,3-cyclohexandiyl,1,4-cyclohexandiyl, 1,3-cycloheptandiyl, 1,5-cycloheptandiyl, etc.

“Oxycycloalkylene” includes oxy a 4 to 7 membered monocyclic alkylene,such as a divalent group selected from the following formulas (7)˜(9):

“A 6 to 10 membered mono or bicyclic aromatic hydrocarbon ring” in RingA includes benzene ring or naphthalene ring.

“A 5 to 10 membered monocyclic or bicyclic heteroaromatic ringcontaining 1 to 3 hetero atoms selected from 0 to 2 nitrogen atoms, 0 or1 oxygen atom and 0 or 1 sulfur atom” in Ring A includes pyrrole ring,pyridine ring, furan ring, thiophene ring, pyrimidine ring, pyridazinering, pyrazine ring, triazine ring, indole ring, benzofuran ring,benzothiophene ring, benzimidazole ring, benzothiazole ring, quinolinering, quinazoline ring, purine ring, etc., preferably pyridine ring,furan ring and thiophene ring.

“The divalent group of a monocyclic 5 to 7 membered saturatedheterocycle containing 1 or 2 hetero atoms selected from 1 or 2 nitrogenatoms, oxygen atom, and sulfur atom (said sulfur atom may be oxidized by1 or 2 oxygen atoms)” in Y² includes pyrrolidindiyl group, piperidindiylgroup, piperazindiyl group, morpholindiyl group, thiomorpholindiylgroup, 1-oxothiomorpholindiyl group, 1,1-dioxothiomorpholindiyl group,etc. and the ring may bind via an optional carbon atom or nitrogen atomwith the adjacent Ring A and Q². Preferable divalent groups of saidsaturated heterocycle containing a nitrogen atom(s) are1,3-pyrrolidindiyl group, 1,4-piperazindiyl group, 1,3-piperazindiylgroup, 1,4-piperidindiyl group, 1,3-piperidindiyl group,2,4-morpholindiyl group, 2,4-thiomorpholindiyl group,1-oxo-2,4-thiomorpholindiyl group, 1,1-dioxo-2,4-thiomorpholindiylgroup, etc.

The substituent by which alkyl group, cycloalkyl group, or alkoxy groupis substituted in R includes halogen atom, hydroxy group, alkoxy group,amino group, alkylamino group, dialkylamino group, etc. Thesubstituent(s) are the same or different and the number of thesubstituent(s) are 1 or plural, preferably 1 to 5. The substituent(s)include chlorine atom, fluorine atom, methoxy group, ethoxy group,propoxy group, dimethylamino group, ethylamino group, etc.

Alkyl group in R includes preferably C₁₋₃ alkyl group, such as methylgroup, ethyl group, propyl group, 1-methylethyl group, etc. Substitutedalkyl group in R includes preferably, trifluoromethyl group,2,2,2-trifluoroethyl group, 2-methoxyethyl group, 2-hydroxyethyl group,2-dimethylaminoethyl group, etc. Alkoxy group in R includes preferablyC₁₋₃ alkoxy group, such as methoxy group, ethoxy group, propoxy group,1-methylethoxy group. Substituted alkoxy group in R includes preferablytrifluoromethoxy group, 2,2,2-trifluoroethoxy group, 2-methoxyethoxygroup, 2-hydroxyethoxy group, 2-dimethylaminoethoxy group, etc.

The substituents of the substituted amino group in R include alkylgroup, alkyl group substituted by hydroxy group, or alkyl groupsubstituted by alkoxy group. The substituent(s) are the same ordifferent, and the number of the substituent(s) is 1 or 2. Thesubstituent(s) include methyl group, ethyl group, propyl group,1-methylethyl group, 2-ethoxyethyl group, 2-hydroxyethyl group,2-ethoxyethyl group, etc. Two substituents of the substituted aminogroup in R may be taken together to form with the adjacent carbon atom a5 to 7 membered heterocycle containing a nitrogen atom(s), and saidheterocycle containing a nitrogen atom(s) includes the same rings as inthe heterocycle containing a nitrogen atom(s) which R¹¹ and R¹² aretaken to form, as mentioned below. Examples thereof are pyrrolidine,N-methylpiperazine, piperidine, morpholine, etc.

Alkylene in Y¹ includes preferably C₁₋₃ alkylene, such as methylene,methylmethylene, ethylene, 1-methylethylene, 2-methylethylene,trimethylene, etc.

Alkylene substituted by oxo group in Y¹ means divalent group in which anoptional methylene constituting of the alkylene is substituted bycarbonyl group, and includes preferably —COCH₂—, —CH₂COCH₂—, and—CH₂CO—.

Alkylene in Y² includes, preferably C₁₋₃ alkylene, such as methylene,ethylene, trimethylene, etc.

Alkylene substituted by hydroxy group or oxo group in Y² means adivalent group in which an optional methylene constituting of thealkylene is substituted by hydroxy group or carbonyl group, and includespreferably, —CHOHCH₂—, —CH₂CHOHCH₂—, —CH₂CHOH—, —COCH₂—, —CH₂COCH₂—, and—CH₂CO—.

Oxyalkylene in Y² includes a divalent group, preferably, such as —OCH₂—,—O(CH₂)₂—, or —O(CH₂)₃— and the oxygen atom in said divalent group isbound to Ring A.

When Y² is divalent group of the following formula:

it may bind in the optional direction.

Alkylene in Z includes preferably C₁₋₃ alkylene, such as methylene,methylmethylene, etc.

Alkoxy group in Q¹ includes preferably, straight or branched C₁₋₄ alkoxygroup, such as methoxy group, ethoxy group, propoxy group, etc.

When Q¹ or Q² is a substituent group selected from the group consistingof the following groups:

—COOR¹⁰; —COSR¹⁰; —OCOOR¹⁰; —OCOR¹⁰; —CONR¹¹R¹²; —OCONR¹¹R¹² (wherein,R¹⁰, R¹¹ and R¹² are the same as defined above); and a group selectingfrom the group of the following formulas (3)˜(6):

wherein M and q are the same as defined above,the substituent group by which alkyl group, alkeny group, alkynyl group,cycloalkyl group or cycloalkeny group in R¹⁰, R¹¹ and R¹² is substitutedincludes halogen atom, hydroxy group, substituted or unsubstitutedalkoxy group, substituted or unsubstituted amino group, substituted orunsubstituted aryl group, or substituted or unsubstituted heteroaromaticgroup, etc. The substituents are the same or different and the number ofthe substituent(s) is 1 or plural, preferably 1 to 5.

The substituent group of the above mentioned substituted amino groupincludes alkyl group, alkyl group substituted by hydroxy group, or alkylgroup substituted by alkoxy group. The substituent(s) are the same ordifferent and the number of the substituent(s) is 1 or 2. Said twosubstituents may be taken to form with the adjacent nitrogen atom a 5 to7 membered heterocycle containing a nitrogen atom(s). Said heterocyclecontaining a nitrogen atom(s) includes the same rings as in theheterocycle containing a nitrogen atom(s) which R¹¹ and R¹² are taken toform, as mentioned below.

The aryl group mentioned above includes phenyl group, 1-naphthyl group,and 2-naphthyl group. The heteroaromatic group mentioned above includes2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furyl group,3-furyl group, etc.

The substituent group on the above substituted aryl group or the abovesubstituted heteroaromatic group includes halogen atom such as chlorineatom, fluorine atom, etc.; hydroxy group; alkyl group such as methylgroup, ethyl group, etc.; alkoxy group, such as methoxy group, ethoxygroup, etc.; amino group; alkylamino group; dialkylamino group; alkylgroup substituted by 1 to 3 halogen atoms such as trifluoromethyl group,etc.

The substituent group of the above substituted alkoxy group includeshalogen atom, such as chlorine atom, fluorine atom, etc.; hydroxy group;alkoxy group, such as methoxy group, ethoxy group, propoxy group. etc.;substituted or unsubstituted aryl group; substituted or unsubstitutedheteroaromatic group, etc. The substituent group of said aryl group orsaid heteroaromatic group is the same as the substituent of alkyl group,etc. in the above R¹⁰, R¹¹, and R¹².

The 5 to 7 membered heterocycle containing a nitrogen atom(s) which R¹¹and R¹² are taken to form with the adjacent nitrogen atom includes a 5to 7 membered saturated heterocycle containing a nitrogen atom(s)containing 1 to 3 hetero atoms selected from 1 or 2 nitrogen atoms, 0 or1 oxygen atom, and 0 or 1 sulfur atom and said sulfur atom may beoxidized by 1 or 2 oxygen atoms. Examples thereof are pyrrolidine,piperazine, piperidine, morpholine, thiomorpholine, 1-oxothiomorpholine,1,1-dioxothiomorpholine, etc. and each of them may be substituted byhydroxy group, carboxy group, alkyl group, alkylcarbonyl group,alkylsulfonyl group, alkoxy group or alkoxycarbonyl group. Saidheterocycle containing a nitrogen atom(s) includes preferably asaturated heterocycle containing a nitrogen atom(s) of the formula (2):

wherein Y³ is a single bond, methylene, oxygen atom, sulfur atom, SO,SO₂, NR¹⁴ (wherein R¹⁴ is hydrogen atom, C₁₋₄ alkyl group, C₂₋₄alkylcarbonyl group, C₂₋₄ alkoxycarbonyl group, or C₁₋₄ alkylsulfonylgroup),

-   q¹ is an integer selected from 0˜4, and-   R¹³ is hydroxy group, carboxy group, C₁₋₄ alkyl group, C₁₋₄ alkoxy    group, or C₂₋₄ alkoxycarbonyl group.

R¹⁰ is preferably substituted or unsubstituted straight or branched C₁₋₆alkyl group. Said substituent includes halogen atom, hydroxy group,alkoxy group, substituted or unsubstituted aryl group, and substitutedor unsubstituted amino group. Examples of R¹⁰ are methyl group, ethylgroup, propyl group, 1-methylethyl group, butyl group, 2-methylpropylgroup, 1-methylpropyl group, 1,1-dimethylethyl group, 2,2-difluoroethylgroup, 2,2,2-trifluoroethyl group, 2-hydroxyethyl group, 3-hydroxypropylgroup, 2-methoxyethyl group, 2-ethoxyethyl group, 2-benzyloxyethylgroup, 2-dimethylaminoethyl group, 2-morpholinoethyl group, etc.

R¹¹ and R¹² are preferably, substituted or unsubstituted straight orbranched C₁₋₆ alkyl group. Said substituent group includes hydroxygroup, alkoxy group, etc. Examples of R¹¹ and R¹² are methyl group,ethyl group, propyl group, 1-methylethyl group, butyl group,2-methylpropyl group, 1-methylpropyl group, 1,1-dimethylethyl group,2-hydroxyethyl group, 3-hydroxypropyl group, 2-methoxyethyl group,2-ethoxyethyl group, etc. Furthermore, a 5 to 7 heterocycle containing anitrogen atom(s) which R¹¹ and R¹² are taken to form with the adjacentnitrogen atom is one of preferable modes, such as pyrrolidine,piperazine, N-methylpiperazine, piperidine, morpholine, etc.

When Q¹ or Q² is an optional substitution group selected from the abovesubstituent groups, it is preferably —COOR¹⁰, —COSR¹⁰, —OCOOR¹⁰, or—CONR¹¹R¹², more preferably —COOR¹⁰. In addition m is preferably 1.

The 9 to 14 membered bi or tricyclic fused ring which R¹⁰ or R¹¹ aretaken to form with the adjacent Ring A in Q² is preferably the groupselected from the following formulas:

wherein Ring A″ is the same as Ring A, and q is an integer selected from1 to 3, more preferably the group of the following formulas:

wherein q is the same as defined above.

The adenine compound of the present invention, according to the kinds ofsubstituents, may include a tautomer, a geometrical isomer, astereoisomer or a mixture thereof.

Namely when at least one asymmetrical carbon atom presents in a compoundof the general formula (1), a diastereomer or an enantiomer exists andthese isolated isomers or a mixture thereof are included in the presentinvention.

In addition, the adenine compound of the general formula (1) and itstautomer are chemically equivalent and the adenine compound of thepresent invention includes the tautomer. Said tautomer is illustrativelyan oxo compound of the general formula (1′):

wherein Ring A, m, n, R, X¹, Y¹, Y², Z, Q¹, and Q² are the same asdefined above.

The pharmaceutically acceptable salt includes acid addition salts orbase addition salts. The acid addition salt includes for example,inorganic salts such as hydrochloride, hydrobromide, hydrosulfate,hydroiodide, nitrate, phosphate, etc., organic salts, such as citrate,oxalate, acetate, formate, propionate, benzoate, trifluoroacetate,maleate, tartarate, methanesulfonate, benzenesulfonate,para-toluenesulfonate, etc. The base addition salt includes inorganicbase salts such as sodium salt, potassium salt, calcium salt, magnesiumsalt, ammonium salt, etc., organic base salts, such as triethylammoniumsalt, triethanolammonium salt, pyridinium salt, diisopropylammoniumsalt, and amino acid salts formed with basic or acidic amino acids suchas arginine, aspartic acid, glutamic acid, etc. The compound of thegeneral formula (1) may form a hydrate(s) or a solvate(s) with ethanol,etc.

The compound of the general formula (1) can be prepared by the followingmethods. The starting materials which are not described below areprepared in accordance with the method described below or the knownmethods described, for example, in WO 98/01448 or WO 99/28321 or inaccordance with the known methods.

wherein in the above formulas, Q³ is Q¹, or carboxy group, Q⁴ is Q²,carboxy group, or hydroxy group, L is a leaving group, and Ring A, m, n,R, X¹, Y¹, Y², Z, Q¹ and Q² are the same as defined above.

A compound (II) is obtained by reacting a compound (I) and a compound(VIII) in the presence of a base.

The base used in this reaction is an alkali metal carbonate such assodium carbonate, potassium carbonate, etc., an alkaline earth metalcarbonate such as calcium carbonate, etc., a metal hydroxide such assodium hydroxide, potassium hydroxide, etc., a metal hydride such assodium hydride, etc., or a metal alkoxide such as potassium t-butoxide,etc. The solvent used in this reaction is a halogenatedhydrocarbon-solvent such as carbon tetrachloride, chloroform, methylenechloride, etc., an ether-solvent such as diethyl ether, tetrahydrofuran,1,4-dioxane, etc., an aprotic solvent such as dimethylformamide,dimethyl sulfoxide, acetonitrile, etc. The reaction is carried out, forexample at the range from about 0° C. to around boiling point of thesolvent.

The compound (IV) is obtained by reaction a compound (II) and a compound(IX).

When X¹ is NR¹, the reaction is carried out in the presence or absenceof a base. The base includes for example, an alkali metal carbonate suchas sodium carbonate, potassium carbonate, etc., an alkaline earth metalcarbonate such as calcium carbonate, etc., a metal hydroxide such assodium hydroxide, potassium hydroxide, etc., an organic base such astriethylamine, diisopropylethylamine, 4-dimethylaminopyridine, etc. Thesolvent used in this reaction is an ether-solvent such astetrahydrofuran, 1,4-dioxane, diglyme, etc., an alcohol-solvent such aspropanol, butanol, etc., an aprotic solvent such as dimethylformamide,etc. The reaction may be carried out in the absence of a solvent. Thereaction is carried out, for example at the range from about 50° C. to200° C.

When X¹ is oxygen atom or sulfur atom, the reaction is carried out inthe presence of a base. The base includes for example, an alkali metalsuch as sodium, potassium, etc., an alkali metal hydride such as sodiumhydride, etc. The solvent used in this reaction is an ether-solvent suchas tetrahydrofuran, 1,4-dioxane, diglyme, etc., an aprotic solvent suchas dimethylformamide, dimethyl sulfoxide, etc. The reaction may becarried out in the absence of a solvent. The reaction is carried out,for example at the range from about 50° C. to 200° C.

Furthermore, in the step from a compound (I) to a compound (IV), first acompound (III) can be synthesized in the same manner as the above methodand then the product (III) can be reacted with a compound (VIII) to givea compound (IV).

A compound (V) can be prepared by brominating a compound (IV). Thebrominating agent is bromine, hydrobromic acid perbromide, N-bromosuccinimide, etc. Sodium acetate may be added as a reaction promoter inthis reaction. The solvent is a halogenated hydrocarbon-solvent such ascarbon tetrachloride, methylene chloride, dichloroethane, etc., anether-solvent such as diethyl ether, etc., acetic acid, carbondisulfide, etc. The reaction is carried out, for example at the rangefrom about 0° C. to around boiling point of the solvent.

A compound (VI) is obtained by reacting a compound (V) with a metalalkoxide such as sodium methoxide, etc.

The solvent is an ether-solvent such as diethyl ether, tetrahydrofuran,1,4-dioxane, etc., an aprotic solvent such as dimethylformamide, etc.,an alcohol solvent such as methanol corresponding to the metal alkoxideused in this reaction and so on. The reaction is carried out, forexample at the range of from room temperature to around boiling point ofthe solvent.

A compound (VII) is obtained by treating a compound (VI) or a compound(V) in an acidic condition.

The acid is for example, an inorganic acid such as hydrochloric acid,hydrobromic acid, sulfuric acid, etc., an organic acid such astrifluoroacetic acid, etc. The solvent is for example, water, a mixtureof water and an organic solvent. Said organic solvent includes anether-solvent such as diethyl ether, tetrahydrofuran, etc., an aproticsolvent such as dimethylformamide, acetonitrile, etc., analcohol-solvent such as methanol, ethanol, etc. The reaction is carriedout, for example at the range from room temperature to around boilingpoint of the solvent.

The compound wherein X¹ is a single bond in a compound of the generalformula (1) can be prepared by the method described in the examples ofthe present specification. The intermediates corresponding to a compound(III) can be prepared in accordance with the method described in theabove WO 98/01448.

wherein Ring A, m, n, R, X¹, Y¹, Y², Z, Q³ and Q⁴ are the same asdefined above, X is amino group, hydroxy group, or mercapto group and Lis a leaving group.

A compound (XII) is obtained by reacting a compound (X) and a compound(XI) in the presence of a base.

The base is for example, an alkali metal carbonate such as sodiumcarbonate, potassium carbonate, etc., an alkaline earth metal carbonatesuch as calcium carbonate, etc., a metal hydroxide, such as sodiumhydroxide, potassium hydroxide, etc., an organic base such astriethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine,etc., a metal alkoxide such as sodium methoxide, etc. The solvent is forexample, a halogenated hydrocarbon-solvent such as methylene chloride,etc., an ether-solvent such as diethyl ether, tetrahydrofuran,1,4-dioxane, etc., an alcohol-solvent such as methanol, ethanol, etc.,an aprotic solvent such as dimethylformamide, dimethyl sulfoxide,acetonitrile, etc. The reaction is carried out, for example at the rangefrom about 0° C. to around boiling point of the solvent.

A compound (XIV) is obtained by reacting a compound (XII) and a compound(XIII) in the presence or absence of a base.

The base is for example, an inorganic base such as an alkali metalcarbonate such as sodium carbonate, potassium carbonate, etc., analkaline earth metal carbonate such as calcium carbonate, etc., a metalhydroxide such as sodium hydroxide, potassium hydroxide, etc., anorganic base such as triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine, etc., a metal alkoxide such as sodiummethoxide, etc. The solvent used in this reaction are an ether-solventsuch as tetrahydrofuran, 1,4-dioxane, diglyme, etc., an alcohol-solventsuch as methanol, ethanol, etc., an aprotic solvent such as toluene,dimethylformamide, dimethyl sulfoxide, etc. The reaction may be carriedout in the absence of a solvent. The reaction is carried out, forexample at the range from room temperature to around boiling point ofthe solvent.

In the step from a compound (XII) to a compound (XIV), compound (XV) canbe synthesized and the product (XV) can be reacted to give a compound(XIV).

A compound (XV) wherein X is amino group is obtained by reacting acompound (XII) and guanidine in the presence or absence of a base. Thebase is, for example, an alkali metal carbonate such as sodiumcarbonate, potassium carbonate, etc., an alkaline earth metal carbonatesuch as calcium carbonate, etc., a metal hydroxide, such as sodiumhydroxide, potassium hydroxide, etc., an organic base such astriethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine,etc., a metal alkoxide such as sodium methoxide, etc. The solvent usedin this reaction are an ether-solvent such as tetrahydrofuran,1,4-dioxane, diglyme, etc., an alcohol-solvent such as methanol,ethanol, etc., an aprotic solvent such as toluene, dimethylformamide,dimethyl sulfoxide, etc. The reaction may be carried out in the absenceof a solvent. The reaction is carried out, for example at the range fromroom temperature to around boiling point of the solvent.

A compound (XV) wherein X is hydroxy group is obtained by reacting acompound (XII) and urea in the presence or absence of a base. The baseis, for example, an alkali metal carbonate such as sodium carbonate,potassium carbonate, etc., an alkaline earth metal carbonate such ascalcium carbonate, etc., a metal hydroxide, such as sodium hydroxide,potassium hydroxide, etc., an organic base such as triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc., a metalalkoxide such as sodium methoxide, etc. The solvent used in thisreaction is an ether-solvent such as tetrahydrofuran, 1,4-dioxane,diglyme, etc., an alcohol solvent such as methanol, ethanol, etc., anaprotic solvent such as toluene, dimethylformamide, dimethyl sulfoxide,etc. The reaction may be carried out in the absence of a solvent. Thereaction is carried out, for example at the range from about roomtemperature to around boiling point of the solvent.

A compound (XV) wherein X is mercapto group is obtained by reacting acompound (XII) and benzoylisocyanate in the presence or absence of abase and then, subjecting the product to cyclization reaction. The baseused in the reaction with benzoisocyanate is for example, an alkalimetal carbonate such as sodium carbonate, potassium carbonate, etc., analkaline earth metal carbonate such as calcium carbonate, etc., anorganic base such as triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine, etc. The solvent used in this reaction is ahalogenated hydrocarbon such as methylene chloride, etc., anether-solvent such as tetrahydrofuran, 1,4-dioxane, etc., an aproticsolvent such as dimethylformamide, dimethyl sulfoxide, etc. The reactionis carried out, for example at the range from about 0° C. to aroundboiling point of the solvent.

The base used in the cyclization reaction is an alkali metal hydroxide,such as sodium hydroxide, potassium hydroxide, etc., a metal alkoxide,such as sodium methoxide, potassium t-butoxide, etc. The solvent is anether-solvent such as tetrahydrofuran, etc., an alcohol-solvent such asethanol, 2-propanol, etc., an aprotic solvent such as,dimethylformamide, dimethyl sulfoxide, etc. The reaction is carried out,for example at the range from about room temperature to around boilingpoint of the solvent.

A compound (XIV) is obtained by reacting a compound (XV) and a compound(XVI) in the presence of a base.

The base is for example, an alkali metal hydrogencarbonate such assodium hydrogencarbonate, etc., an alkali metal carbonate such as sodiumcarbonate, potassium carbonate, etc., an alkaline earth metal carbonatesuch as calcium carbonate, etc., a metal hydroxide, such as sodiumhydroxide, potassium hydroxide, etc., a metal hydride such as sodiumhydride, etc., an organic base such as triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine, etc., a metalalkoxide such as potassium t-butoxide, etc. The solvent used in thisreaction is a halogenated hydrocarbon such as carbon tetrachloride,chloroform, methylene chloride, etc., an ether-solvent such as diethylether, tetrahydrofuran, 1,4-dioxane, etc., an aprotic solvent such as,dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. The reactionis carried out, for example from the range from about 0° C. to aroundboiling point of the solvent.

Process 3

When Q³ or Q⁴ is carboxy group or hydroxy group in the above generalformulas (II)˜(XVI), it can be converted to Q¹ or Q², respectively inthe known method to the skilled person in the art or the similar method,for example, the method described in R. C. Larock “Comprehensive OrganicTransformation (VCH Publishers, Inc, 1989)”.

The reaction is concretely explained below.

(1) When Q¹ or Q² is —COOR¹⁰:

After an intermediate of the compound of the present invention, namely acarboxylic acid is converted to an acid halide, the acid halide isreacted with R¹⁰OH to give an ester. The halogenating agent is forexample, thionyl chloride, phosphoryl chloride, phosphoruspentachloride, phosphorus trichloride, etc. The solvent is for example,a halogenated hydrocarbon such as carbon tetrachloride, chloroform,methylene chloride, etc., an ether-solvent such as diethyl ether,tetrahydrofuran, 1,4-dioxane, etc., an aprotic solvent such as, toluene,xylene, etc. The reaction is carried out, for example from the rangefrom about 0° C. to around boiling point of the solvent. The base usedin the esterification reaction is for example, an organic base such astriethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine,etc. The solvent is for example, a halogenated hydrocarbon such asmethylene chloride, etc., an ether-solvent such as diethyl ether,tetrahydrofuran, etc., an aprotic solvent such as, dimethylformamide,dimethyl sulfoxide, etc. The reaction is carried out, for example fromthe range from about 0° C. to around boiling point of the solvent.

(2) When Q¹ or Q² is —CONR¹¹R¹²:

After an intermediate of the compound of the present invention, namely acarboxylic acid is converted to an acid halide, the acid halide isreacted with R¹¹R¹²NH to give an amide. The caboxylic acid and R¹¹R¹²NHcan be condensed to give the amide, too. The base used in the reactionwith the acid halide is for example, an alkali metal carbonate such assodium carbonate, potassium carbonate, etc., an alkaline earth metalcarbonate such as calcium carbonate, etc., a metal hydroxide, such assodium hydroxide, potassium hydroxide, etc., a metal hydride such assodium hydride, etc., an organic lithium compound such as butyllithium,an organic base such as triethylamine, diisopropyl ethylamine, pyridine,4-dimethylaminopyridine, etc. The solvent used in this reaction is ahalogenated hydrocarbon such as methylene chloride, etc., anether-solvent such as diethyl ether, tetrahydrofuran, etc., an aproticsolvent such as, dimethylformamide, dimethyl sulfoxide, etc. Thereaction is carried out, for example at the range from about 0° C. toaround boiling point of the solvent.

The condensation reaction may be carried out in the presence of anactive esterification agent. The condensing agent is, for example, acarbodiimide compound such as1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride,dicyclohexylcarbodiimide, etc. The esterification agent is, for example,N-hydroxybenztriazole, N-hydroxysuccinimide, etc. The solvent is ahalogenated hydrocarbon such as chloroform, methylene chloride, etc., anether-solvent such as diethyl ether, tetrahydrofuran, etc., an aproticsolvent such as, dimethylformamide, dimethyl sulfoxide, etc. Thereaction is carried out, for example at the range from about 0° C. toaround boiling point of the solvent.

(3) When Q¹ or Q² is —OCOOR¹⁰, —OCOR¹⁰ or —OCONR¹¹R¹²:

The intermediate of the compound of the present invention, namely ahydroxy group and L¹COOR¹⁰, L¹COR¹⁰, or L¹CONR¹¹R¹² (wherein L¹ is aleaving group, preferably halogen atom, R¹⁰, R¹¹ and R¹² are the same asdefined above) are reacted in the presence of a base to give a carbonatederivative, an acyl compound and a urethane derivative, respectively.The base is, for example, an organic base such as triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine. The solvent isa halogenated hydrocarbon such as methylene chloride, etc., anether-solvent such as diethyl ether, tetrahydrofuran, etc., an aproticsolvent such as dimethylformamide, dimethyl sulfoxide, etc. The reactionis carried out, for example, at the range from about 0° C. to aroundboiling point of the solvent.

(4) When Q¹ or Q² is any one of the formulas (3)˜(6):

In case of the formula (3) or (4) being a lactone ring, said compound isprepared by treating a hydroxycarboxylic acid with an acid. The acid isan inorganic acid such as, hydrochloric acid, hydrobromic acid, sulfuricacid, etc., or an organic acid such as methanesulfonic acid,p-toluenesulfonic acid, etc. An acid anhydride such as acetic acidanhydride can be also used. The solvent is water, an organic solvent ora mixture of water and the organic solvent. The organic solvent is anether-solvent such as diethyl ether, tetrahydrofuran, etc., an aproticsolvent such as benzene, acetonitrile, etc. The reaction is carried out,for example at the range from about room temperature to around boilingpoint of the solvent.

In case of the formula (5) or (6) being a cyclic carbonate, saidcompound is prepared by reacting a dihydroxy compound with tri phosgenein the presence of a base. The base is an organic base, such astriethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine,etc. The solvent is a halogenated hydrocarbon such as chloroform,methylene chloride, etc., an ether-solvent such as diethyl ether,tetrahydrofuran, etc., an aprotic solvent such as, benzene, toluene,etc. The reaction is carried out, for example at the range from about 0°C. to around boiling point of the solvent.

Any compound used in process 1 or 2 can use as a starting material ineach step described in process 3 and each step described in process 3may use any steps described in process 1 or 2, as long as it does notinfluence the reaction in the post process.

When the adenine compound of the present invention, its intermediate orits starting material has a functional group, the introduction of thesubstituent group or the conversion reaction into the functional groupcan be carried out in accordance of the conventional method known in theart, if necessary, in an appropriate step, namely a step in the middleof process 1 or 2. These methods are described in Jikken Kagaku Kozaedited by Nippon Kagakukai, Maruzen, or Comprehensive OrganicTransformations, by R. C. Lalock (VCH Publishers, Inc, 1989), etc. Asthe conversion reaction into the functional group, acylation orsulfonylation by using an acid halide, an sulfonyl halide, etc.,alkylation by using an alkyl halide, etc., hydrolysis, Friedel-CraftsReaction or C to C bond-formation reaction such as Wittig reaction,etc., oxidization or reduction reaction, etc. are illustrated.

Furthermore, when the compound of the present invention or theintermediate thereof has a functional group such as amino group, carboxygroup, hydroxy group, oxo group, etc., the compound may be subjected toprotection or deprotection reaction, if necessary. The preferableprotecting groups, the protecting methods and the deprotecting methodsare in detail explained in Protective Groups in Organic Synthesis 2ndEdition (John Wiley & Sons, Inc.; 1990) and so on.

The compound of the general formula (1) of the present invention and theintermediate for preparing it can be purified by the method known in theart such as column chromatography (e.g., silica gel chromatography, ionexchange chromatography), recrystallization, etc. The solvent forrecrystallization includes an alcohol-solvent such as methanol, ethanol,2-propanol, etc., an ether-solvent such as ethyl ether, etc., anester-solvent such as ethyl acetate, etc., an aromatic hydrocarbonsolvent such as benzene, toluene, etc., a ketone-solvent such asacetone, etc., a hydrocarbon-solvent such as hexane etc., an aproticsolvent such as dimethylformamide, acetonitrile, water or a mixturethereof. Other purification methods are explained in Jikken Kagaku KozaVol. 1 (edited by Nippon Kagaku Kai, Maruzen).

The compound of the general formula (1) of the present invention whichhas one or more asymmetric centers can be prepared by the conventionalmethod by using a starting material having an asymmetric carbon atom(s),or otherwise in a way of the process for the preparation by introducingthe asymmetric center(s). For example, the enantiomer compound can beprepared by using an optically active compound as a starting compound orby optical resolution in an appropriate way of the process for thepreparation. The optical resolution is carried out by the diastereomarmethod, namely by salt-forming the compound of the general formula (1)of the present invention or an intermediate thereof with an opticallyactive acid such as a monocarboxylic acid (e.g., mandelic acid,N-benzyloxyalanine, lactic acid, etc.), a dicarboxylic acid (e.g.,tartaric acid, o-diisopropylidene tartaric acid, malic acid, etc.), asulfonic acid (e.g., camphorsulfonic acid, bromocamphorsulfonic acid,etc.) in an inert solvent such as an alcohol-solvent (e.g., methanol,ethanol, 2-propanol, etc.), an ether-solvent (e.g., diethyl ether,etc.), an ester solvent (e.g., ethyl acetate, etc.), ahydrocarbon-solvent (e.g., toluene, etc.), an aprotic solvent (e.g.,acetonitrile, etc.), or a mixture thereof.

The compound of the general formula (1) of the present invention or anintermediate thereof which has an acidic functional group such ascarboxy group, can be prepared by salt-forming with an optically activeamine (an organic amine such as a-phenethylamine, kinin, quinidine,cinchonidine, cinchonine, strychnine, etc.).

The salt formation is carried out at the range from room temperature tothe boiling temperature of the solvent. In order to promote the opticalpurity of the object compound, it is preferable to raise once thetemperature to around the boiling point of the solvent. The yield can beraised by cooling the reaction mixture, if necessary, before filtratinga crystallized precipitate. The amount of the optically active acid oramine is preferably about 0.5 to about 2.0 moles per a substrate, morepreferably around 1 mole. The precipitate is, if necessary,recrystallized from an inert solvent such as an alcohol-solvent (e.g.,methanol, ethanol, 2-propanol, etc.), an ether-solvent (e.g., ethylether, etc.), an ester-solvent (e.g., ethyl acetate, etc.), ahydrocarbon-solvent (e.g., toluene, etc.), an aprotic solvent (e.g.,acetonitrile, etc.), a mixture thereof to give an optically purifiedcompound. Furthermore, if necessary, an optically resolved salt istreated with an acid or a base by the conventional method to give a freeform.

The adenine compound of the present invention, and a tautomer thereof,or a pharmaceutically acceptable salt thereof shows interferon inductingactivity, and/or IL-4 and IL-5 production suppressing activity, andtherefore, is effective as a prophylactic or therapeutic agent for viraldiseases, allergic diseases, or dermatosis. Furthermore, the adeninecompound of the present invention, a tautomer thereof, or apharmaceutically acceptable salt thereof is characterized in, whentopically administered, showing an medical effect at the applied lesion,but in systematically showing none of the pharmacological activitybecause the compound is converted by an enzyme in vivo to other compound(degraded compound) having substantially reduced medical effect andtherefore, is useful as a topically administered agent. The medicaleffect used herein means a pharmacological activity of the compound,such as interferon inducing activity, IL-4 production suppressingactivity and/or IL-5 production suppressing activity, etc.

The medical effect of the degraded compound is preferably 10 times, morepreferably 100 times, further more preferably 1000 times reducedcomparing with that of the parent compound.

Said pharmacological activities can be evaluated by the conventionalmeasuring method known in the art, preferably by the measuring method invitro. For example, there are illustrated methods described in Method inENZYMOLOGY (Academic press), etc. or the method by using thecommercialized ELISA Kit (e.g., AN′ ALYSA (Immunoassay System), etc.),or the method described in Example of the present specification, etc.

For example, by measuring interferon inducing activity with bioassayusing cells of mouse spleen, the amount of each interferon induction(IU)/ml at the same concentration of the parent compound (the compoundof the present invention) and the degraded compound can be compared. Inaddition, each concentration showing the definite amount of interferonproduction can be compared with the parent compound and its degradedcompound, too.

As a pharmacological activity, the activity in vivo caused by interferoninducing activity, etc. is illustrated. Said activity in vivo includesimmune activating activity, influenza-like symptom, etc. The immuneactivating activity includes the induction of cytotoxic activity such asNK cells, etc. The influenza-like symptom includes fever, etc. The fevermeans the rise of the body temperature of a mammalian, for example, incase of human, the fever means that the body temperature rises more thannormal temperature. The topical administration method is not limited,and the administration is done in case of administration via nasalcavity, alveolus or air way, by aeration or inhalation, in case ofadministration to skin, by spreading on the skin, and in case ofadministration to eye, by eye dropping, etc. Preferable administrationis done by aeration or inhalation.

It can be also confirmed that the compound of the present specification,when it is topically administered, is converted to a degraded compoundin the blood, etc. in human or animal for example, by its half life inthe serum or in liver S9 in vitro. The test method to determine the halflife of the compound of the present invention in vitro is known.

The above “degraded compound” means a compound having carboxy group orhydroxy group which is prepared by hydrolyzing the amide bond or esterbond contained in the subsistent(s), Q¹ and/or Q² in the general formula(1).

The measuring method of the half life in liver S9 of the compound of thepresent invention is as follows:

The compound of the present invention is added to liver S9 solution, andthe mixture is incubated at 37±0.5° C. for 5 minutes to 2 hours. Byquantitatively analyzing at the definite interval the amount of thecompound of the present invention remaining in the liver S9 solutionwith HPLC (high performance liquid chromatography), etc., the constantof quenching velocity is calculated and the half life is calculated. Theliver S9 means the supernatant prepared by the liver of mammalian beinghomogenated in an aqueous solution, such as physiological saline,sucrose solution, KCl solution, etc., the homogenate being centrifugedat 9000×g and its supernatant fraction being collected. The aqueoussolution is usually used 2 to 4 times as much as the amount of liver.The liver of human, dog, rabbit, guinea pig, rat, mouse, etc. are used.The liver S9 diluted with buffer, etc., if necessary can be used.

The measuring method of the half life in the serum of the compound ofthe present invention is as follows:

The compound of the present invention is added to the serum solution,and the mixture is incubated at 37±0.5° C. for 5 minutes to 2 hours. Byquantitatively analyzing at the definite interval the amount of thecompound of the present invention remaining in the serum solution withHPLC (high performance liquid chromatography), etc., the constant ofquenching velocity calculated and the half life is calculated. Themethod described in Example is illustrated.

The serum herein means the supernatant fraction obtained by excludinghemocytes and blood coagulation factor from blood by centrifugation,etc. The serum diluted with buffer, etc. can be used.

The compound of the present invention is not limited as long as thecompound is formed into the preparation for topical administration. Thepreparation is prepared by the conventional known method and thepreparation may contain ordinal carriers, excipients, binders,stabilizers, buffer, solubilizing agents, isotonic agents, etc.

Examples of the preparation for topical administration are ointments,lotion, creams, gels, tapes, dermal patches, poultices, sprays,aerosols, or aqueous solutions/suspensions for spray used for inhalatoror cartridge for insufflator, eye drops, nose drops, powders for topicaladministration, etc.

The ointments, creams and gels usually contain 0.01 to 10 w/w % of thecompound of the present invention. An aqueous or oil base used in themmay contain suitable viscosity-increasing agents and/or gelling agentsand/or solvents. Said base includes for example, water and/or liquidparaffin or an oil such as squalane, various fatty acid esters,vegetable oils such as arachis oil, castor oil, animal oils such assqualene or polyethylene glycol. The viscosity-increasing agent andgelling agent include soft paraffin, aluminium stearate, cetostearylalcohol, polyethylene glycol, sheep wool fat, beeswax, carboxy methyleneand cellulose derivative and/or non-ionic emulsifying agent such asglycerin monostearate.

The lotion usually contains 0.01 to 10 w/w % of the compound of thepresent invention and the lotion preparation may be formulated by anaqueous or oil base and may usually contain an emulsifying agent, astabilizer, a dispersion agent, a suspension agent, or aviscosity-increasing agent.

The powder for external administration usually contains 0.01 to 10 w/w %of the compound of the present invention and may be made of suitablebases such as talc, lactose or starch.

The eye drop preparation may be formed by an aqueous or nonaqueous baseand may contain a dispersing agent, a solubilizing agent, a suspendingagent or a preservative.

The splay may be formed into an aqueous solution or suspension by forexample, using a suitable liquid jet, or into aerosols distributed froma pressured bag such as a measuring inhalator.

The aerosol suitable for inhalation is either a suspension or a solutionand may usually contain the compound of the present invention and asuitable jet such as fluorocarbon, hydrogen-containingchlorofluorocarbon or a mixture thereof, especially hydrofluoroalkane,more especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoron-propane or a mixture thereof. The aerosol may further contain, ifnecessary, excipients well known in the art, such as a surfactant suchas oleic acid or lecithin and a co-solvent such as ethanol.

A gelatin capsule or cartridge used for inhalator or for insufflator maybe formed by using a powdered mixture and a suitable powdered base suchas lactose or starch, etc., for inhalating the compound of the presentinvention. Each capsule or cartridge may usually contain 20 μg˜10 mg ofthe compound of the present invention. As another method, the compoundof the present invention may be administered without any excipients suchas lactose.

The amount of the compound of the present invention contained in thepreparation for external administration depends on the kind ofpreparations, but is generally 0.001 to 10% by weight, preferably 0.005to 1% by weight. In case of the powder for inhalation, the amount of thecompound of the present invention is a range of 0.1 to 5% by weight.

In regard to the aerosol each a measured amount or one blown (splayed)amount of the compound of the present invention is preferably 20 μg to2000 μg, preferably about 20 μg to 500 μg. The dosage is once or severaltimes (for example, 2 to 4 or 8 times) a day. One to three dose unitsare administered per each time.

The composition of the present invention may be administered incombination with other therapeutically effective medicament. Whenadministered as an antiasthma, the composition of the present inventioncan be used in a combination with a β2-adrenaline receptor agonist, anantihistamine or an antiallergic agent, especially a β2-adrenalinereceptor agonist. The each medicament used in a combination may beadministered at the same time or different time separately or in theform of a mixture thereof.

EXAMPLE

The present invention is explained in detail by illustrating Examplesand Reference examples below, but should not be limited by them.

Reference Example 1 2-Butoxyadenine

After sodium (13.56 g, 590 mmol) was dissolved in n-butanol (480 ml),2-chloroadenine (4.0 g, 23.59 mmol) was added thereto and the mixturewas stirred at 140° C. for 19 hours. After the mixture was allowed tocool, water (400 ml) was added thereto and the mixture was stirred for30 minutes. And then the organic layer was separated and concentrated.Water (400 ml) was added to the residue and the solution was neutralizedwith concentrated hydrochloric acid. The resulting precipitate wasfiltered and washed with ethanol to give the captioned compound (3.72 g,17.97 mmol, yield 76%) as a white solid.

Reference Example 2 Methyl 3-bromomethylbenzoate

3-Bromomethylbenzoyl chloride (1.96 g, 10.37 mmol) was dissolved inmethanol (20 ml), and triethylamine (1.5 ml) was added thereto. Themixture was stirred at room temperature for 1 hour. The mixture waspoured into a saturated sodium hydrogencarbonate solution and wasextracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate and concentrated to give the captionedcompound (1.90 g, 10.29 mmol, yield: 97%) as a colorless oil.

Reference Example 3 2-Butoxy-9-(3-methoxycarbonylbenzyl)adenine

After 2-butoxyadenine (0.66 g, 3.19 mmol) obtained by Reference example1 and potassium carbonate (0.80 g, 5.79 mmol) were added to DMF (40 ml),the compound (1.99 g, 10.78 mmol) obtained by Reference example 2 wasadded thereto and the mixture was stirred at room temperature for 18hours. After removing the solvent the residue was poured into water andextracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=300/1˜50/1) to give the captioned compound (0.50 g, 1.41mmol, yield: 44%) as a white solid.

Reference Example 4 8-Bromo-2-butoxy-9-(3-methoxycarbonylbenzyl)adenine

After 2-butoxy-9-(3-methoxycarbonylbenzyl)adenine (0.41 g, 1.54 mmol)obtained by Reference example 3, and sodium acetate (1.14 g, 13.90 mmol)were dissolved in acetic acid (50 ml), bromine (0.1 ml, 7.7 mmol) wasadded thereto. The mixture was stirred at room temperature for 5 hours.After removing the solvent the residue was poured into water andextracted with dichloromethane. After the organic layer was washed witha saturated sodium hydrogencarbonate solution, a saturated sodiumhydrogensulfite solution and saturated brine in that order, the organiclayer was dried over anhydrous magnesium sulfate and concentrated togive the captioned compound (0.45 g, 1.04 mmol, yield: 90%) as a yellowtar.

Reference Example 5 2-Butoxy-9-(3-carboxybenzyl)-8-methoxyadenine

After sodium (0.49 g, 21.30 mmol) was dissolved in methanol (50 ml),8-bromo-2-butoxy-9-(3-methoxycarbonylbenzyl)adenine (0.22 g, 0.51 mmol)obtained by Reference example 4 was added thereto and the mixture wasrefluxed for 30 hours. After being allowed to cool, the solution wasneutralized with concentrated hydrochloric acid and concentrated. Theresidue was poured into water. The resulting precipitate was filteredand washed with methanol to give the captioned compound (0.13 g, 0.35mmol, yield: 69%) as a white solid.

Reference Example 6 2-n-Butylaminoadenine

2-Chloroadenine (6.0 g, 35.4 mmol) and n-butylamine (30 ml) were reactedin an autoclave (200 ml) at 130° C. for 150 hours. After the reactionmixture was concentrated under reduced pressure, the residue was pouredinto water to precipitate the solid. The precipitated solid wassuccessively washed with methylene chloride and methanol to give thecaptioned compound (2.08 g, yield 30%) as a yellowish orange powderedsolid.

Reference Example 7 9-Benzyl-2-(2-hydroxyethylamino)adenine

9-Benzyl-2-chloroadenine (1.0 g, 3.8 mmol) was stirred in 2-aminoethanol(8 ml) at 110° C. for 4 hours. Water (100 ml) was added to the reactionmixture and the resulting precipitate was filtered to give the captionedcompound (1.1 g, 3.8 mmol, yield: 100%) as a white solid.

Reference Example 8 9-Benzyl-8-bromo-2-(2-hydroxyethylamino)adenine

9-Benzyl-2-(2-hydroxyethylamino)adenine (100 mg, 0.35 mmol) obtained byReference example 7 was dissolved in acetic acid and thereto was added2.0 M bromine/acetic acid (0.18 ml, 0.36 mmol). The mixture was stirredat room temperature for 3 hours. After adding water (3 ml) to thereaction mixture, the solution was neutralized with 40% sodium hydroxidesolution under ice cooling and the resulting precipitate was filtered togive the captioned compound (130 mg, 0.36 mmol, yield: 100%) as a whitesolid.

Reference Example 92-(2-Hydroxyethylamino)-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was prepared in accordance with the method ofReference example 7.

Reference Example 108-Bromo-2-(2-hydroxyethylamino)-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was prepared in accordance with the method ofReference example 8.

Reference Example 112-(2-Hydroxyethoxy)-9-{(6-methyl-3-pyridyl)methyl}adenine)

After sodium (2.1 g, 91 mmol) was dissolved in ethylene glycol (30 ml),2-chloro-9-{(6-methyl3-pyridyl)methyl}adenine (3.0 g, 11 mmol) was addedthereto and the mixture was stirred at 100° C. for 3 hours. After themixture was allowed to cool, water (80 ml) was added thereto and theresulting precipitate was filtered to give the captioned compound (3.1g, 10 mmol, yield: 94%) as a white solid.

Reference Example 128-Bromo-2-(2-hydroxyethoxy)-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was prepared in accordance with the method ofReference example 8.

Reference Example 132-(2-Hydroxyethoxy)-8-methoxy-9-{(6-methyl-3-pyridyl)methyl}adenine

After 8-bromo-2-(2-hydroxyethoxy)-9-{(6-methyl-3-pyridyl)methyl}adenine(2.3 g, 7.7 mmol) obtained by Reference example 12 was suspended in amixture of 1N sodium hydroxide solution (30 ml) and methanol (30 ml),the mixture was stirred at 100° C. for 10 hours. Water was added to thereaction mixture and the mixture was extracted with chloroform. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated to give the captioned compound (670 mg, 2.0 mmol, yield:26%) as a pale yellow solid.

Reference Example 142-{2-(N,N-Dimethylaminocarbonyloxy)ethoxy}-8-methoxy-9-{(6-methyl-3-pyridyl)methyl}adenine

2-(2-Hydroxyethoxy)-8-methoxy-9-{(6-methyl-3-pyridyl)methyl}adenine (200mg, 0.61 mmol) obtained by Reference example 13, dimethylaminopyridine(5 mg, 0.4 mmol) and N,N-diisopropylethylamine (0.32 mmol, 1.8 mmol)were dissolved in a mixed solvent of pyridine (2 ml) anddimethylformamide (2 ml), and thereto was added under ice coolingN,N-dimethylcarbamoyl chloride (1.1 ml, 12 mmol). The mixture wasstirred for 21 hours. Water was added to the reaction mixture and themixture was extracted with chloroform. The organic layer was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography to give the captioned compound (66mg, 0.16 mmol, yield: 27%) as a white solid.

Reference Example 15 9-Benzyl-8-hydroxy-2-thioadenine

After aminomalononitrile p-toluenesulfonate (45 g, 178 mmol) was addedto tetrahydrofuran, thereto were added benzylisocyanate (25 g, 188 mmol)and N,N-diisopropylethylamine (23.5 ml, 130 mmol). The mixture wasstirred at room temperature for 14 hours. After removing the solvent,the residue was poured into water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentrated.To the residue were added tetrahydrofuran and 1N sodium hydroxidesolution. The mixture was stirred at 50° C. for 20 minutes andneutralized with 15% potassium hydrogensulphate. The resultingprecipitate was filtered, added to tetrahydrofuran and thereto wasdropped benzoylisothiocyanate (41 ml, 305 mmol). The mixture was stirredat room temperature over a night and the solvent was removed. Theprecipitate was collected by adding ether to the residue, refluxed in amixed solvent of tetrahydrofuran and 2N sodium hydroxide solution for 50hours and neutralized with 10% potassium hydrogensulfate solution. Theresulting precipitate was collected and recrystallized from ethylacetate to give the captioned compound as a white powdered solid.

Reference Example 162-(2,3-Dihydroxypropylamino)-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was prepared in accordance with the method ofReference example 7.

Reference Example 178-Bromo-2-(2,3-dihydroxypropylamino)-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was prepared in accordance with the method ofReference example 10.

Reference Example 182-(2,3-Dihydroxypropylamino)-8-methoxy-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was prepared in accordance with the method ofReference example 13.

Reference Example 198-Methoxy-9-{(6-methyl-3-pyridyl)methyl}-2-{(2-oxo-1,3-dioxolan-4-yl)methylamino}adenine

2-(2,3-Dihydroxypropylamino)-8-methoxy-9-{(6-methyl-3-pyridyl)methyl}adenine(230 mg, 0.64 mmol) obtained by Reference example 18,4-dimethylaminopyridine (5 mg, 0.04 mmol) and triethylamine (0.02 ml,0.14 mmol) were dissolved in dimethylformamide (2 ml). Thereto was addeddi-t-butyl dicarbonate (410 mg, 1.9 mmol) in the oil bath kept at 50° C.and the mixture was stirred for 14 hours. The reaction mixture wasconcentrated and the residue was purified by preparative thin layerchromatography to give the captioned compound (64 mg, 0.17 mmol, yield26%) as a white solid.

Reference Example 20 9-Benzyl-2-methoxycarbonylmethoxyadenine

9-Benzyl-8-hydroxy-2-(2-hydroxyethoxy)adenine (0.39 g, 1.37 mmol) andpyridinium dichromate (5.28 g, 14.03 mmol) were dissolved in DMF (14 ml)and the solution was stirred at room temperature for 23 hours. Thereaction mixture was poured into an aqueous saturated ammonium chloridesolution, and extracted with chloroform. The organic layer wasconcentrated and the resulting residue was added to methanol (100 ml).Thereto was added sulfuric acid (5 ml) and the mixture was refluxedunder stirring for 3 hours. The mixture was neutralized with sodiumhydrogencarbonate in an ice bath and extracted with chloroform. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography (SiO₂ 20g, eluting solvent: CHCl₃/MeOH=300/1˜100/1) to give the captionedcompound (0.12 g, 0.38 mmol) as a white solid.

Reference Example 21 9-Benzyl-8-bromo-2-methoxycarbonylmethoxyadenine

9-Benzyl-2-methoxycarbonylmethoxyadenine (0.12 g, 0.38 mmol) obtained byReference example 20 and sodium acetate (57 mg, 0.69 mmol) weredissolved in chloroform (6 ml), and thereto was added bromine (92 mg,0.58 mmol) in an ice bath. The mixture was stirred at room temperaturefor 5 hours. After removing the solvent, the residue was poured intowater and extracted with chloroform. The organic layer was successivelywashed with a saturated sodium hydrogencarbonate and 10% sodiumthiosulfate, dried over anhydrous magnesium sulfate and thenconcentrated. The residue was purified by column chromatography (SiO₂ 20g, eluting solvent: CHCl₃/MeOH=200/1) to give the captioned compound(0.10 g, 0.25 mmol) as a white solid.

Reference Example 22 2-(2-Methoxycarbonylethyl)adenine

9-Benzyl-2-(2-methoxycarbonylethyl)adenine (0.29 g, 0.93 mmol) obtainedby Example 61 and 20% Pd(OH)₂/C (0.32 g) were added to a mixed solventof isopropanol (8 ml) and formic acid (8 ml), and the mixture wasstirred at a pressure of 2 atmosphere of hydrogen at 70° C. for 40hours. After filtration, the filtrate was concentrated to give thecaptioned compound (0.23 g, 0.86 mmol) as a white solid.

Reference Example 232-(2-Methoxycarbonylethyl)-9-{(6-methyl-3-pyridyl)methyl}adenine

2-(2-Methoxycarbonylethyl)adenine (313 mg, 1.51 mmol) obtained byReference example 22 and potassium carbonate (0.44 g, 3.18 mmol) wereadded to DMF (40 ml). The mixture was at 70° C. for 1 hour and thencooled to room temperature. Thereto was added 6-methyl-3-pyridylmethylchloride hydrochloride (0.38 g, 2.13 mmol) and the mixture was stirredat room temperature for 15 hours. After removing the solvent, theresidue was poured into water and extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by column chromatography (SiO₂ 20 g, elutingsolvent: CHCl₃/MeOH=100/1˜30/1) to give the captioned compound (358 mg,1.15 mmol) as a white solid.

Reference Example 248-Bromo-2-(2-methoxycarbonylethyl)-9-{(6-methyl-3-pyridyl)methyl}adenine

After 2-(2-methoxycarbonylethyl)-9-{(6-methyl-3-pyridyl)methyl}adenine(70 mg, 0.21 mmol) obtained by Reference example 23 and sodium acetate(0.35 g, 4.27 mmol) were dissolved in acetic acid (8 ml), thereto wasadded bromine (0.34 g, 2.13 mmol) and the mixture was stirred at 70° C.for 9 hours. After removing the solvent, the residue was poured intowater and extracted with dichloromethane. The organic layer was washedwith saturated sodium hydrogencarbonate, saturated sodium thiosulfate,and saturated brine in that order and then dried over anhydrousmagnesium sulfate. The residue was purified by column chromatography(SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=100/1˜40/1) to give thecaptioned compound (31 mg, 0.076 mmol) as a pale yellow solid.

Reference Example 252-Butoxy-8-hydroxy-9-(5-methoxycarbonylfurfuryl)adenine

Lithium aluminium hydride (54 mg, 1.42 mmol) was added to THF (4 ml),and thereto butoxy-8-hydroxy-9-(5-methoxycarbonylfurfuryl)adenine (62mg, 0.17 mmol) obtained by Example 15 in THF (10 ml) was dropped in anice bath. The mixture was stirred at room temperature for 1 hour.Thereto were added water (54 μl), 1N sodium hydroxide (162 μl) and water(162 μl) in that order in an ice bath. The reaction mixture was filteredand the filtrate was concentrated. The residue was purified by columnchromatography (SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=30/1˜20/1) togive the captioned compound (50 mg, 0.15 mmol) as a white solid.

Reference Example 26 2-Butoxy-9-(5-cyanomethylfurfuryl)-8-hydroxyadenine

After 2-butoxy-8-hydroxy-9-(5-hydroxymethylfurfuryl)adenine (42 mg, 0.13mmol) obtained by Reference example 25 was dissolved in chloroform (10ml), thereto was added thionyl chloride (0.2 ml) and the mixture wasrefluxed for 2 hours. After removing the solvent, the residue wasdissolved in DMF (5 ml). Thereto was added sodium cyanide (35 mg, 0.71mmol) and the mixture was stirred at room temperature for 4 hours. Afterremoving the solvent, the residue was poured into water, neutralizedwith 1N hydrochloric acid and extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by column chromatography (SiO₂ 20 g, elutingsolvent: CHCl₃/MeOH=50/1˜30/1) to give the captioned compound (31 mg,0.091 mmol) as a white solid.

Reference Example 27 3,4-Dimethoxycarbonylbenzyl bromide

After 3,4-dimethoxycarbonyltoluene (5.28 g, 25.36 mmol) was added tocarbon tetrachloride (250 ml), thereto were added N-bromosuccinimide(6.33 g, 35.56 mmol) and benzoylperoxide (0.53 g, 2.19 mmol) and themixture was refluxed for 10 hours under stirring. After removing thesolvent, the residue was poured into water and extracted with ether. Thecombined organic layer was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography (SiO₂250 g, eluting solvent: Hexane/CHCl₃=10/1˜CHCl₃ only) to give thecaptioned compound (2.05 g, 7.14 mmol) as a colorless transparent oil.

Reference Example 28 2-Butoxy-9-(3,4-dimethoxycarbonylbenzyl)adenine

2-Butoxyadenine (0.50 g, 2.41 mmol) obtained by Reference example 1 andpotassium carbonate (0.25 g, 1.81 mmol) were added to DMF (12 ml) andthe mixture was stirred at 70° C. for 1 hour. After the mixture wascooled to room temperature, 4-dimethoxycarbonylbenzyl bromide obtainedby Reference example 27 (1.99 g, 10.78 mmol) was added thereto and themixture was stirred at room temperature for 9 hours. After removing thesolvent, the residue was poured into water and extracted withchloroform. The organic layer was dried over anhydrous magnesium sulfateand concentrated. The residue was purified by column chromatography(SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=300/1˜100/1) to give thecaptioned compound (775 mg, 1.88 mmol) as a pale yellow solid.

Reference Example 292-Butoxy-8-methoxy-9-{(6-methoxycarbonyl-3-pyridyl)methyl}adenine

2-Butoxy-9-{(6-carboxyl-3-pyridyl)methyl}-8-methoxyadenine (87 mg, 0.23mmol), potassium carbonate (32 mg, 0.24 mmol) and methyl iodide (66 mg,0.46 mmol) were added in DMF (10 ml), and the mixture was stirred atroom temperature for 3 hours. After removing the solvent, the residuewas poured into water and extracted with chloroform. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated. The residue was purified by column chromatography(SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=100/1) to give the captionedcompound (78 mg, 0.20 mmol) as a yellow tar.

Reference Example 30 2-Butoxy-9-{6-thio-3-pyridyl}methyl)adenine

2-Butoxy-9-{6-chloro-3-pyridyl}methyl}-8-hydroxyadenine (1.00 g, 3.00mmol) and 70% NaSH nH2O (3.40 g) were added to DMF (35 ml) and themixture was stirred at 120° C. for 9 hours. After removing the solvent,the residue was poured into water and neutralized with concentratedhydrochloric acid. The resulting precipitate was filtered, successivelywashed with water and chloroform and dried in vacuo under heating togive the captioned compound (0.98 g, 2.97 mmol) as a yellow solid.

Reference Example 312-Butoxy-9-{6-(γ-butyrolactonyl)thio-3-pyridyl}methyl)adenine

2-Butoxy-9-{6-thio-3-pyridyl}methyl)adenine (0.25 g, 0.76 mmol) obtainedby Reference example 30, potassium carbonate (78 mg, 0.51 mmol) andα-bromo-γ-butyrolactone (190 mg, 1.15 mmol) were added to DMF (18 ml),and the mixture was stirred at room temperature for 17 hours. Afterremoving the solvent, the residue was poured into water and extractedwith chloroform. The organic layer was washed with saturated brine,dried over anhydrous magnesium sulfate and concentrated. The residue waspurified by column chromatography (SiO₂ 10 g, eluting solvent:CHCl₃/MeOH=200/1˜50/1) to give the captioned compound (0.31 g, 0.75mmol) as a white solid.

Reference Example 328-Bromo-2-butoxy-9-{4-(γ-butyrolactonyloxy)benzyl}adenine

8-Bromo-2-butoxy-9-(4-hydroxybenzyl)adenine (0.20 g, 0.51 mmol), cesiumcarbonate (0.42 g, 1.29 mmol) and α-bromo-γ-butyrolactone (0.42 g, (2.55mmol) were added to DMF (7 ml), and the mixture was stirred at roomtemperature for 55 hours. After removing the solvent, the residue waspoured into water and extracted with chloroform. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography (SiO₂ 10g, eluting solvent: CHCl₃/MeOH=300/1˜100/1) to give the captionedcompound (0.19 g, 0.40 mmol) as a yellow tar.

Reference Example 33 2-(2-Methoxyethoxy)adenine

After sodium (3.00 g, 130 mmol) was dissolved in 2-methoxyethanol (150ml), thereto was added 2-chloroadenine (3.00 g, 17.69 mmol) and themixture was refluxed for 8 hours. After the mixture was allowed to cool,water (400 ml) was added thereto and neutralized with concentratedhydrochloric acid. The resulting precipitate was filtered and washedwith methanol to give the captioned compound (3.06 g, 14.48 mmol, yield73%) as a white solid.

Reference Example 34(9-(3-Methoxycarbonylmethylbenzyl)-2-(2-methoxyethoxy)adenine

2-(2-Methoxyethoxy)adenine (0.19 g, 0.90 mmol) obtained by Referenceexample 33 and potassium carbonate (0.87 g, 6.30 mmol) were added to DMF(10 ml) and the mixture was stirred at 60° C. for 1.5 hours. Aftercooling to room temperature, methyl 3-bromo methylphenylacetate (0.44 g,1.80 mmol) was added thereto and the mixture was stirred at roomtemperature for 1.5 hours. After removing the solvent, the residue waspoured into 5% citric acid and extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by column chromatography (SiO₂ 6.0 g, elutingsolvent: CHCl₃/MeOH=200/1˜50/1) to give the captioned compound (0.23 g,0.63 mmol, yield; 70%) as a pale yellow solid.

Reference Example 358-Bromo-9-(3-methoxycarbonylmethylbenzyl)-2-(2-methoxyethoxy)adenine

After 9-(3-methoxycarbonylmethylbenzyl)-2-(2-methoxyethoxy)adenine (0.23g, 0.63 mmol) obtained by Reference example 34 and sodium acetate (0.093g, 1.13 mmol) were dissolved in chloroform (10 ml), bromine (0.15 g,0.95 mmol) was added thereto and the mixture was stirred at roomtemperature for 3 hours. After removing the solvent, the residue waspoured into water and extracted with chloroform. The organic layer waswashed with saturated sodium hydrogencarbonate, saturated sodiumhydrogen sulfite, and saturated brine in that order and dried overanhydrous magnesium sulfate. The residue was purified by columnchromatography (SiO₂ 7.0 g, eluting solvent: CHCl₃/MeOH=100/0˜200/1) togive the captioned compound (0.22 g, 0.50 mmol, yield: 79%) a brownsolid.

Reference Example 362-Butylamino-9-(3-methoxycarbonylmethylbenzyl)adenine

2-Butylaminoadenine (0.21 g, 1.00 mmol) obtained by Reference example 6and potassium carbonate (0.69 g, 5.00 mmol) were added to DMF (7 ml),and thereto was added methyl 3-bromomethylphenylacetate (0.49 g, 2.00mmol). The mixture was stirred at room temperature for 2 hours. Afterremoving the solvent, the residue was poured into 5% citric acid andextracted with chloroform. The organic layer was dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography (SiO₂ 6.3 g, eluting solvent: CHCl₃/MeOH=100/0˜50/1) togive the captioned compound (0.23 g, 0.61 mmol, yield: 61%) as a whitesolid.

Reference Example 378-Bromo-2-butylamino-9-(3-methoxycarbonylmethylbenzyl)adenine

After 2-butylamino-9-(3-methoxycarbonylmethylbenzyl)adenine obtained byReference example 36 (0.23 g, 0.61 mmol) was dissolved in chloroform (10ml), bromine (0.15 g, 0.92 mmol) was added thereto and the mixture wasstirred at room temperature for 1 hour. After removing the solvent, theresidue was poured into water and extracted with chloroform. The organiclayer was washed with saturated sodium hydrogencarbonate, saturatedsodium hydrogensulfite and saturated brine in that order, dried overanhydrous magnesium sulfate and concentrated to give the captionedcompound (0.23 g, 0.51 mmol, yield: 83%) as a pale yellow solid.

Reference Example 38 2-Chloro-9-(3-methoxycarbonylmethylbenzyl)adenine

2-Chloroadenine (1.70 g, 10.0 mmol) and potassium carbonate (9.67 g,70.0 mmol) were added to DMF (35 ml) and the mixture was stirred at 60°C. for 1.5 hours. After cooling to room temperature, methyl3-bromomethylphenylacetate (3.16 g, 13.0 mmol) was added thereto and themixture was stirred at room temperature for 1.5 hours. After removingthe solvent, thereto was added chloroform (50 ml) and the resultingsolid was washed with water to give the captioned compound (2.13 g, 6.41mmol, yield: 64%) as a pale yellow solid.

Reference Example 398-Bromo-2-chloro-9-(3-methoxycarbonylmethylbenzyl)adenine

After 2-chloro-9-(3-methoxycarbonylmethylbenzyl)adenine obtained byReference example 38 (2.00 g, 6.03 mmol) and sodium acetate (2.95 g,36.0 mmol) were dissolved in chloroform (100 ml), bromine (4.79 g, 30.0mmol) was added thereto and the mixture was stirred at room temperaturefor 5 hours. After removing the solvent, the residue was poured intowater and extracted with chloroform. The organic layer was washed withsaturated sodium hydrogencarbonate, saturated sodium hydrogensulfite andsaturated brine in that order, dried over anhydrous magnesium sulfateand concentrated to give the captioned compound (1.78 g, 4.34 mmol,yield: 72%) as a brown solid.

Reference Example 40 Methyl 2-(4-bromomethyl)phenylpropionate

Thionyl chloride (5.80 ml, 80 mmol) was added to methanol (100 ml) underice cooling and the mixture was stirred for 1 hour. Thereto was dropped2-(4-bromomethyl)phenylpropionic acid (4.86 g, 20 mmol) in methanol (30ml). After stirring at room temperature for 2 hours, the solvent wasremoved. Water was added to the residue and the mixture was extractedwith ethyl acetate. The organic layer was washed with 5% sodiumcarbonate and 5% brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography(hexane-ethyl acetate) to give the captioned compound (4.71 g, 18.3mmol, yield: 92%) as a colorless oil.

Reference Example 41 Ethyl α,α-dimethyl-m-tolylacetate

After potassium t-butoxide (11.22 g, 50 mmol) was added to ethylm-tolylacetate (7.12 g, 40 mmol) and iodomethane (14.20 g, 100 mmol) inTHF solution (300 ml) at −80° C., the mixture was stirred at roomtemperature for 3 hours. After saturated ammonium chloride solution (200ml) was added thereto, the solvent was removed and the residue wasextracted with chloroform. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated. The residue waspurified by column chromatography (hexane-ethyl acetate) to give thecaptioned compound (4.92 g, 23.9 mmol, yield: 84%) as a colorless oil.

Reference Example 42 Ethyl α,α-dimethyl-m-bromomethylphenylacetate

To ethyl α,α-dimethyl-m-tolylacetate (4.12 g, 20 mmol) obtained byReference example 41 in carbon tetrachloride (140 ml) were addedN-bromosuccinimide (3.56 g, 20 mmol) and benzoylperoxide (100 mg, 0.41mmol) and the mixture was refluxed for 3 hours. To the reaction mixturewas 5% sodium hydrogensulfite and the organic layer was separated. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by columnchromatography (hexane-ethyl acetate) to give the captioned compound(4.62 g) as a colorless oil.

Reference Example 43 Methyl 4-(2-bromoethyl)benzoate

Thionyl chloride (5.80 ml, 80 mmol) was added to methanol (100 ml) underice cooling. The mixture was stirred for 1 hour and thereto was dropped2-(4-bromoethyl)benzoic acid (4.58 g, 20 mmol) in methanol (30 ml).After stirring at room temperature for 2 hours, the solvent was removed.Water was added to the residue and mixture was extracted with ethylacetate. The organic layer was washed with 5% sodium carbonate and 5%brine, dried over anhydrous magnesium sulfate and concentrated to givethe captioned compound (4.79 g, 18.3 mmol, yield: 99%) as a colorlessoil.

The compounds of Reference examples 44˜46 below were obtained inaccordance with the method of Reference example 40.

Reference Example 44 Methyl o-tolylacetate (4.36 g, 26.6 mmol, yield:89%) Reference Example 45 Methyl p-tolylacetate (4.42 g, 27.0 mmol,yield: 90%) Reference Example 46 Methyl 2-fluoro-5-methylbenzoate (3.07g, 18.3 mmol, yield: 91%) Reference Example 47 Methyl2-methoxy-5-methylbenzoate

To 5-methylsalicylic acid (3.04 g, 20 mmol) in DMF (100 ml) were addedpotassium carbonate (8.28 g, 60 mmol) and iodomethane (6.24 g, 44 mmol)under ice cooling and then the mixture was stirred at room temperaturefor 12 hours. The mixture were extracted by adding 5% sodiumhydrogensulfite and ethyl acetate, and the extracted organic layer waswashed with 5% citric acid and 5% brine. The organic layer was driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by column chromatography (hexane-ethyl acetate) to give thecaptioned compound (3.43 g, 19.1 mmol, yield: 95%) as a colorless oil.

Reference Example 48 Methyl α,α-dimethyl-p-tolylacetate

The captioned compound was obtained in accordance with the method ofExample 41 (2.26 g, 11.8 mmol, yield: 75%).

Reference Example 49 Ethyl(2R,S)-3-methylphenylpropionate

To ethyl m-tolylacetate (3.56 g, 20 mmol) in THF (300 ml) was addediodomethane (3.12 g, 22 mmol). Thereto at −80° C. was added potassiumt-butoxide (2.47 g, 22 mmol) and the mixture was stirred at roomtemperature for 3 hours. After saturated ammonium chloride (200 ml) wasadded thereto at −80° C., THF was removed and the residue was extractedwith chloroform. The organic layer was dried over anhydrous magnesiumsulfate, concentrated and purified by column chromatography(hexane-ethyl acetate) to give the captioned compound (2.97 g, 15.5mmol, yield: 77%) as a colorless oil.

The compounds of Reference examples 50˜54 below were prepared inaccordance with the method of Reference example 42.

Reference Example 50 Methyl o-bromomethylphenylacetate Reference Example51 Methyl 3-bromomethyl-6-fluorobenzoate Reference Example 52 Methyl3-bromomethyl-6-methoxybenzoate Reference Example 53 Methylα,α-dimethyl-p-bromomethylphenylacetate Reference Example 54Ethyl(2R,S)-3-bromomethylphenylpropionate Reference Example 55 Methyldimethoxy(3-methylphenyl)acetate

To 3-methylacetophenone (5.0 g, 37 mmol) in pyridine (50 ml) was addedselenium dioxide (7.44 g, 67 mmol), and the mixture was refluxed for 3.5hours. The resulting black solid was filtered off. The filtrate wasneutralized with concentrated hydrochloric acid and extracted with etherto give 3-methylphenylglyoxylic acid (6.12 g, 37 mmol, yield: 100%).Then to the obtained 3-methylphenyloxoacetic acid (4.0 g, 24 mmol) inmethanol (250 ml) was added concentrated sulfuric acid (13 ml), and themixture was refluxed for 5 hours. After being neutralized with saturatedsodium hydrogencarbonate, the solution was extracted with chloroform.The organic layer was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography (SiO₂170 g, eluting solvent: Hex/AcOEt=200/1˜0/1) to give the captionedcompound (3.75 g, 16.7 mmol, yield: 69%) as a pale yellow oil.

Reference Example 56 Methyl dimethoxy(3-bromomethylphenyl)acetate

The captioned compound was obtained in accordance with the method ofReference example 27. Yield: 69%

Reference Example 572-Butoxy-9-[3-(1,1,2-trimethoxy-2-oxoethyl)benzyl]adenine

The captioned compound as a yellow solid was obtained in accordance withthe method of Reference example 3, yield: 75%.

Reference Example 588-Bromo-2-butoxy-9-[3-(1,1,2-trimethoxy-2-oxoethyl)benzyl]adenine

The captioned compound was obtained in accordance with the method ofReference example 21, yield: 95%.

Example 1 2-Butoxy-8-hydroxy-9-(3-methoxycarbonylbenzyl)adenine

After 2-butoxy-8-methoxy-9-(3-carboxybenzyl)adenine (0.60 g, 1.61 mmol)obtained by Reference example 5 was dissolved in methanol (20 ml),thereto was added sulfuric acid (1 ml) and the solution was refluxed for1 hour under stirring. After the reaction mixture was neutralized withsaturated sodium hydrogencarbonate solution in an ice bath, theresulting precipitate was filtered and washed with methanol to give thecaptioned compound (0.48 g, 1.29 mmol, yield: 80%) as a white solid.

The compounds of Examples 2˜4 below were obtained in accordance with themethod of Example 1.

Example 2 2-Butoxy-8-hydroxy-9-(3-ethoxycarbonylbenzyl)adenine Example 32-Butoxy-8-hydroxy-9-(3-isopropoxycarbonylbenzyl)adenine Example 42-Butoxy-8-hydroxy-9-{3-(2,2,2-trifluorroethoxycarbonyl)benzyl}adenineExample 52-Butoxy-8-hydroxy-9-{3-(2-benzyloxyethoxycarbonyl)benzyl}adenine

After 2-butoxy-9-(3-carboxybenzyl)-8-methoxyadenine (0.06 g, 0.16 mmol)obtained by Reference example 5 and triethylamine (0.03 g, 0.28 mmol)were added to acetonitrile (10 ml), benzyl 2-bromoethyl ether (0.06 g,0.28 mmol) was added thereto, and the mixture was refluxed for 50 hoursunder stirring. After removing the solvent, the residue was poured intowater and extracted with dichloromethane. The organic layer was driedover anhydrous magnesium sulfate and concentrated. The solid was addedto methanol (10 ml) and concentrated hydrochloric acid (10 ml), and themixture was stirred at room temperature for 18 hours. After neutralizingwith saturated sodium hydrogencarbonate solution, the solution wasextracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate, concentrated and washed with methanol togive the captioned compound (0.03 g, 0.06 mmol, yield: 38%) as a whitesolid.

Example 62-Butoxy-8-hydroxy-9-{3-(2-hydroxyethoxycarbonyl)benzyl}adenine

2-Butoxy-8-hydroxy-9-{3-(2-benzyloxyethoxycarbonyl)benzyl}adenine (0.03g, 0.06 mmol) obtained by Example 5, 5% Pd/C (60 mg) and concentratedhydrochloric acid (0.1 ml) were added to a mixed solvent of THF (30 ml)and methanol (30 ml), and the mixture was stirred under hydrogenatmosphere at room temperature for 60 hours. The reaction mixture wasfiltered, neutralized with saturated sodium hydrogencarbonate solutionand extracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=100/1˜50/1) and washed with methanol to give the captionedcompound (0.01 g, 0.02 mmol, yield: 42%) as a white solid.

The compounds of Examples 7˜9 below were obtained in accordance with themethod of Example 5.

Example 72-Butoxy-8-hydroxy-9-{3-(2-dimethylaminoethoxycarbonyl)benzyl}adenineExample 82-Butoxy-8-hydroxy-9-{3-(2-morpholinoethoxycarbonyl)benzyl}adenineExample 92-Butoxy-8-hydroxy-9-{3-(3-pyridylmethoxycarbonyl)benzyl}adenine Example10 2-Butoxy-8-hydroxy-9-{3-(S-methylthiocarbonyl)benzyl}adenine

After 2-butoxy-9-(3-carboxybenzyl)-8-methoxyadenine (0.06 g, 0.16 mmol)obtained by Reference example 5 and triethylamine (0.02 g, 0.19 mmol)were added to DMF (10 ml), methanesulfonyl chloride (0.02 g, 0.19 mmol)was added thereto in an ice bath, and the mixture was stirred for 1hour. Methanethiol (0.1 ml, 1.43 mmol) was added thereto and the mixturewas stirred at room temperature for 8 hours. After removing the solvent,the residue was poured into water and extracted with dichloromethane.The organic layer was dried over anhydrous magnesium sulfate andconcentrated. The solid was added to methanol (10 ml) and concentratedhydrochloric acid (10 ml) and the mixture was refluxed under stirring atroom temperature for 18 hours. After being neutralized with saturatedsodium hydrogencarbonate solution, the solution was extracted withdichloromethane. The organic layer was dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by columnchromatography (SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=80/1˜20/1) andwashed with methanol to give the captioned compound (0.01 g, 0.03 mmol,yield: 16%) as a white solid.

The compounds of Examples 11˜12 below were obtained in accordance withthe method of Example 1.

Example 11 2-Butoxy-8-hydroxy-9-(4-methoxycarbonylbenzyl)adenine Example12 2-Butoxy-8-hydroxy-9-(4-isopropoxycarbonylbenzyl)adenine Example 132-Butoxy-8-hydroxy-9-{4-(3-pyridylmethoxycarbonyl)benzyl}adenine

After 2-butoxy-9-(4-carboxybenzyl)-8-methoxyadenine (0.05 g, 0.13 mmol)prepared in accordance with the method of Reference example 5 andpotassium carbonate (0.03 g, 0.22 mmol) were added to DMF (10 ml),3-chloromethylpyridine hydrochloride (0.03 g, 0.18 mmol) was addedthereto, and the mixture was stirred at room temperature for 18 hours.After removing the solvent, the residue was poured into water andextracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=300/1˜30/1) and the resulting solid was added to methanol (10ml) and concentrated hydrochloric acid (10 ml). The mixture was stirredat room temperature for 18 hours. After being neutralized with saturatedsodium hydrogencarbonate, the solution was extracted withdichloromethane. The organic layer was dried over anhydrous magnesiumsulfate, concentrated and washed with methanol to give the captionedcompound (0.03 g, 0.07 mmol, yield: 52%) as a white solid.

Example 14 2-Butoxy-8-hydroxy-9-(4-benzyloxycarbonylbenzyl)adenine

The captioned compound was prepared in accordance with the method ofExample 13.

The compounds of Examples 15˜18 below were prepared in accordance withthe method of Example 1.

Example 15 2-Butoxy-8-hydroxy-9-(5-methoxycarbonylfurfuryl)adenineExample 16 2-Butoxy-8-hydroxy-9-(5-isopropoxycarbonylfurfuryl)adenineExample 172-Butoxy-8-hydroxy-9-{(6-methoxycarbonyl-3-pyridyl)methyl}adenineExample 182-Butoxy-8-hydroxy-9-{(6-isopropoxycarbonyl-3-pyridyl)methyl}adenineExample 19 2-Butoxy-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine

Lithium aluminium hydride (0.08 g, 2.15 mmol) was added to THF (10 ml),and thereto was dropped 2-butoxy-9-(3-methoxycarbonyl)benzyladenine(0.20 g, 0.56 mmol) obtained by Reference example 3 in THF (10 ml) in anice bath, and the mixture was stirred at room temperature for 2 hours.Thereto were dropped water (0.1 ml), 5% sodium hydroxide solution (0.3ml) and water (0.3 ml) in that order in an ice bath. After the reactionmixture was filtered, the filtrate was concentrated and the residue waspurified by column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=100/1˜30/1) to give 2-butoxy-9-(3-hydroxymethylbenzyl)adenine(0.18 g, 0.55 mmol, yield: 98%) as a white solid.

2-Butoxy-9-(3-hydroxymethylbenzyl)adenine (0.09 g, 0.27 mmol),triethylamine (0.20 g, 1.98 mmol), tosyl chloride (0.30 g, 1.57 mmol)and pyridine (0.4 ml) were added to DMF (10 ml), and the mixture wasstirred at room temperature for 24 hours. To the reaction mixture wasadded sodium cyanide (0.40 g, 9.16 mmol), and the mixture was stirred at80° C. for 18 hours. After removing the solvent, the residue was pouredinto water and extracted with dichloromethane. The organic layer wasdried over anhydrous magnesium sulfate, concentrated and the residue waspurified by column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=100/1) to give 2-butoxy-9-(3-cyanomethylbenzyl)adenine (0.04g, 0.12 mmol, yield: 44%) as a white solid.

2-Butoxy-9-(3-cyanomethylbenzyl)adenine (0.04 g, 0.12 mmol) was added toa mixed solvent of 5% sodium hydroxide solution (10 ml) and methanol (10ml), and the mixture was stirred at 80° C. for 19 hours. Afterextracting with dichloromethane, the aqueous layer was neutralized withconcentrated hydrochloric acid, and concentrated. The residue andsulfuric acid (1 ml) were added to methanol (50 ml), and the mixture wasrefluxed under stirring for 1 hour. After being neutralized withsaturated sodium hydrogencarbonate solution in an ice bath, the solutionwas extracted with dichloromethane. The combined organic layer was driedover anhydrous magnesium sulfate and concentrated to give2-butoxy-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine (0.04 g,0.11 mmol, yield: 92%) as a pale yellow solid. And then the captionedcompound was obtained in accordance with the method of Example 1, yield(three steps): 71%.

The compounds of Examples 20˜21 below were obtained in accordance withthe method of Example 1.

Example 20 2-Butoxy-8-hydroxy-9-(4-methoxycarbonylmethylbenzyl)adenineExample 212-Butoxy-8-hydroxy-9-(4-isopropoxycarbonylmethylbenzyl)adenine Example22 2-Butoxy-8-hydroxy-9-(4-methoxycarbonylmethoxybenzyl)adenine

8-Bromo-2-butoxy-9-(4-acetoxybenzyl)adenine (0.29 g, 0.67 mmol) obtainedin accordance with the method of Reference example 4 was added tomethanol (10 ml) and 5% sodium hydroxide solution (10 ml), and themixture was stirred at room temperature for 4 hours. After the mixturewas neutralized with concentrated hydrochloric acid, the resulting solidwas filtered and washed with methanol to give8-bromo-2-butoxy-9-(4-hydroxybenzyl)adenine (0.19 g, 0.49 mmol, yield:73%) as a white solid. Thus obtained8-bromo-2-butoxy-9-(4-hydroxybenzyl)adenine (0.05 g, 0.13 mmol) andpotassium carbonate (0.02 g, 0.14 mmol) were added to DMF (10 ml), andthen thereto was added ethyl bromoacetate (0.04 g, 0.24 mmol). Themixture was stirred at room temperature for 18 hours. After removing thesolvent, the residue was poured into water and extracted withdichloromethane. The combined organic layer was dried over anhydrousmagnesium sulfate, and concentrated. The residue was purified by columnchromatography (SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=100/1˜50/1) togive 8-bromo-2-butoxy-9-(4-ethoxycarbonylmethoxybenzyl)adenine (0.06 g,0.12 mmol, yield: 96%) as a white solid. And then the captioned compoundwas obtained in accordance with the method of Example 1, Yield: 80%.

Example 232-Butoxy-8-hydroxy-9-{3-bromo-4-(methoxycarbonylmethoxy)benzyl}adenine

After 2-butoxyadenine (0.11 g, 0.53 mmol) obtained by Reference example1 and potassium carbonate (0.05 g, 0.36 mmol) were added to DMF (10 ml),4-(chloromethyl)phenol acetate (0.12 g, 6.50 mmol) was added thereto,and the mixture was stirred at room temperature for 18 hours. Afterremoving the solvent, the residue was poured into water and extractedwith dichloromethane. The organic layer was dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by columnchromatography (SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=300/1˜30/1) togive 2-butoxy-9-(4-acetoxybenzyl)adenine (0.08 g, 1.41 mmol, yield: 42%)as a white solid. Thus obtained solid was added to methanol (10 ml) and5% sodium hydroxide solution (10 ml), and the mixture was stirred atroom temperature for 2 hours. After being neutralized with concentratedhydrochloric acid, the solution was extracted with dichloromethane. Thecombined organic layer was dried over anhydrous magnesium sulfate andconcentrated to give 2-butoxy-9-(4-hydroxybenzyl)adenine (0.06 g, 0.19mmol. yield: 86%) as a white solid. Thus obtained solid and potassiumcarbonate (0.02 g, 0.14 mmol) were added to DMF (10 ml), and thenthereto was added ethyl bromoacetate (0.04 g, 0.24 mmol). The mixturewas stirred at room temperature for 18 hours. After removing thesolvent, the residue was poured into water and extracted withdichloromethane. The combined organic layer was dried over anhydrousmagnesium sulfate, concentrated and the residue was purified by columnchromatography (SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=100/1˜50/1) togive 2-butoxy-9-{4-(ethoxycarbonyl methoxy)benzyl}adenine (0.06 g, 0.15mmol, yield: 79%) as a white solid. And then the captioned compound wasobtained in accordance with the method of Example 1.

Example 242-Butoxy-8-hydroxy-9-{6-(4-ethoxycarbonyl-1-piperidyl)-3-pyridylmethyl}adenine

2-Butoxy-9-(6-chloro-3-pyridylmethyl)-8-methoxyadenine (0.28 mg, 0.77mmol) was added to 4-ethoxycarbonylpiperidine (10 ml), and the mixturewas refluxed under stirring for 8 hours. After the mixture was allowedto cool, ethanol was added thereto. The resulting solid was filtered andpurified by column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=80/1˜20/1) to give the captioned compound (0.15 g, 1.41 mmol,yield: 44%) as a white solid.

Example 252-Butoxy-8-hydroxy-9-{6-(3-ethoxycarbonyl-1-piperidyl)-3-pyridylmethyl}adenine

The captioned compound was obtained in accordance with the method ofExample 24.

Example 262-Butoxy-8-hydroxy-9-{(6-ethoxycarbonylmethoxy-2-naphthyl)methyl}adenine)

The captioned compound was obtained in accordance with the method ofExample 5.

The compounds of Examples 27˜28 below were obtained in accordance withthe method of Example 1.

Example 27 2-Butylamino-8-hydroxy-9-(4-methoxycarbonylbenzyl)adenineExample 28 2-Butylamino-8-hydroxy-9-(5-ethoxycarbonylfurfuryl)adenineExample 29 9-Benzyl-8-hydroxy-2-methoxycarbonylmethyladenine

After sodium cyanide (0.20 g, 4.08 mmol) and9-benzyl-2-chloromethyl-8-hydroxyadenine (0.20 g, 0.69 mmol) were addedto DMF (10 ml), the mixture was stirred at 80° C. for 7 hours. Afterremoving the solvent, the residue was poured into water and the solutionwas neutralized with concentrated hydrochloric acid. The solution wasextracted with dichloromethane, and the organic layer was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=100/1˜50/1) and washed with methanol to give9-benzyl-2-cyanomethyl-8-hydroxyadenine (0.16 g, 0.57 mmol) as a paleyellow solid. Thus obtained 9-benzyl-2-cyanomethyl-8-hydroxyadenine(0.08 g, 0.29 mmol) was added to a mixed solvent of 5% sodium hydroxidesolution (20 ml) and methanol (10 ml), and the mixture was stirred at60° C. for 8 hours. After the mixture was neutralized with concentratedhydrochloric acid, the solvent was removed. The residue and sulfuricacid (1 ml) were added to methanol (50 ml), and the mixture was refluxedfor 3 hours under stirring. After being neutralized with saturatedsodium hydrogencarbonate solution in an ice bath, the solution wasextracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedwith column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=100/1˜30/1) and washed with methanol to give the captionedcompound (0.02 g, 0.06 mmol) as a white solid.

Example 30 9-Benzyl-2-ethoxycarbonylmethyl-8-hydroxyadenine

The captioned compound was obtained in accordance with the method ofExample 29.

Example 31 9-Benzyl-8-hydroxy-2-methoxycarbonylmethylaminoadenine

9-Benzyl-2-chloroadenine (0.30 g, 1.12 mmol), glycine methyl esterhydrochloride (0.72 g, 5.73 mmol) and diisopropylethylamine (1.48 g,11.47 mmol) were added to n-butanol (10 ml), and the mixture was stirredin an autoclave at 150° C. for 19 hours. The solvent was removed and theresidue was poured into water. The solution was extracted withdichloromethane. The organic layer was dried over anhydrous magnesiumsulfate, concentrated and the residue was purified by columnchromatography to give 9-benzyl-2-methoxycarbonylmethylaminoadenine(0.06 g) as a brown tar. Thus obtained9-benzyl-2-methoxycarbonylmethylaminoadenine was dissolved indichloromethane (10 ml) and to the solution was added bromine (0.05 ml)in an ice bath. The mixture was stirred at room temperature for 1 hour.After removing the solvent, the residue was poured into water andextracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate, concentrated and the residue was purifiedby column chromatography to give9-benzyl-8-bromo-2-methoxycarbonylmethylaminoadenine (0.06 g) as ayellow solid.

Thus obtained 9-benzyl-8-bromo-2-methoxycarbonylmethylaminoadenine wasadded to concentrated hydrochloric acid (10 ml), and the mixture wasstirred for 8 hours at 100° C. The mixture was neutralized in an icebath with 5% sodium hydroxide solution (pH 7) and the solvent wasremoved. To the residue were added methanol (30 ml) and sulfuric acid (1ml), and the mixture was refluxed for 4 hours. After being neutralized(pH 6) in an ice bath with saturated sodium hydrogencarbonate solution,the solution was extracted with dichloromethane. The organic layer wasdried over anhydrous magnesium sulfate, and concentrated. The residuewas purified by column chromatography and the obtained compound waswashed with methanol to give the captioned compound (0.02 g) as a whitesolid.

Example 328-Hydroxy-2-methoxycarbonylmethylamino-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was obtained in accordance with the method ofExample 31.

Example 332-(2-Acetoxyethylamino)-8-hydroxy-9-{(6-methyl-3-pyridyl)methyl}adenine

To8-hydroxy-2-(2-hydroxyethylamino)-9-{(6-methyl-3-pyridyl)methyl}adenine(100 mg, 0.32 mmol) prepared by Comparative example 10 in pyridine (1ml) was added under ice cooling acetic anhydride (0.033 ml, 0.35 mmol),and the mixture was stirred for 3 hours. To the reaction mixture wasadded sodium hydrogen carbonate solution, and the mixture was extractedwith chloroform. The organic layer was dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by preparativethin-layer chromatography to give the captioned compound (14 mg, 0.039mmol, yield: 12%) as a white solid.

The compounds of Examples 34-35 below were obtained in accordance withthe method of Example 33.

Example 348-Hydroxy-2-(2-methoxycarbonyloxyethylamino)-9-{(6-methyl-3-pyridyl)methyl}adenineExample 35 2-(2-Acetoxyethylamino)-9-benzyl-8-hydroxyadenine Example 362-(2-Acetoxyethoxy)-8-hydroxy-9-{(6-methyl-3-pyridyl)methyl}adenine

To 8-hydroxy-2-(2-hydroxyethoxy)-9-[(6-methyl-3-pyridyl)methyl]adenine(90 mg, 0.29 mmol) obtained by Comparative example 11 anddimethylaminopyridine (5 mg, 0.4 mmol) in pyridine (2 ml) was addedunder ice cooling acetic anhydride (0.027 ml, 0.29 mmol), and themixture was stirred for 15 hours. To the reaction mixture was addedwater, and the solution was extracted with chloroform. The combinedorganic layer was dried over anhydrous magnesium sulfate, concentratedand the residue was purified by silica gel column chromatography to givethe captioned compound (11 mg, 0.031 mmol, yield: 11%) as a white solid.

Example 378-Hydroxy-9-(6-methyl-3-pyridyl)methyl-2-{2-(propionyloxy)ethoxy}adenine

The captioned compound was obtained in accordance with the method ofExample 36.

Example 382-{2-(Methoxycarbonyloxy)ethoxy}-8-hydroxy-9-{(6-methyl-3-pyridyl)methyl}adenine

To 8-hydroxy-2-(2-hydroxyethoxy)-9-{(6-methyl-3-pyridyl)methyl}adenine(90 mg, 0.29 mmol) obtained by Comparative example 11 in pyridine (2 ml)was added under ice cooling methyl chloroformate (0.022 ml, 0.29 mmol),and the mixture was stirred for 3 hours. To the reaction mixture wasadded water, and the solution was extracted with chloroform. Thecombined organic layer was dried over anhydrous magnesium sulfate andconcentrated to give the captioned compound (68 mg, 0.18 mmol, yield:63%) as a white solid.

Example 392-{2-(N,N-Dimethylaminocarbonyloxy)ethoxy}-8-hydroxy-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was obtained in accordance with the method ofComparative example 11.

Example 40 9-Benzyl-8-hydroxy-2-(methoxycarbonylmethyl)thioadenine

After 9-benzyl-8-hydroxy-2-thioadenine (200 mg, 0.73 mmol) obtained byReference example 7 was dissolved in dimethylformamide (8 ml), theretowere added potassium carbonate (150 mg, 1.1 mmol) and methylbromoacetate (0.1 ml, 1.1 mmol) in that order, and the mixture wasstirred at room temperature for 2 hours. After removing the solvent, theresidue was poured into water and the solution was extracted withchloroform. The combined organic layer was dried over anhydrousmagnesium sulfate, concentrated and the residue was purified by silicagel column chromatography to give the captioned compound (173 mg, yield:69%) as a white solid.

The compounds of Examples 41-59 below are obtained in accordance withthe method of Example 40.

Example 41 9-Benzyl-2-(ethoxycarbonylmethyl)thio-8-hydroxyadenineExample 42 9-Benzyl-8-hydroxy-2-(octyloxycarbonylmethyl)thioadenineExample 43 9-Benzyl-2-(t-butoxycarbonylmethyl)thio-8-hydroxyadenineExample 44 2-(Allyloxycarbonylmethyl)thio-9-benzyl-8-hydroxyadenineExample 45 2-(Benzyloxycarbonylmethyl)thio-9-benzyl-8-hydroxyadenineExample 46 9-Benzyl-2-(2-fluoroethoxycarbonylmetyl)thio-8-hydroxyadenineExample 479-Benzyl-2-(2,2-difluoroethoxycarbonylmetyl)thio-8-hydroxyadenineExample 489-Benzyl-2-(2,2,2-trifluoroethoxycarbonylmetyl)thio-8-hydroxyadenineExample 499-Benzyl-8-hydroxy-2-(2-methoxyethoxycarbonylmethyl)thioadenine Example50 9-Benzyl-2-(ethylcarbamoylmethyl)thio-8-hydroxyadenine Example 519-Benzyl-8-hydroxy-2-(1-piperidinocarbonylmethyl)thioadenine Example 529-Benzyl-8-hydroxy-2-(morphorinocarbonylmethyl)thioadenine Example 539-Benzyl-8-hydroxy-2-(1-ethoxycarbonylethyl)thioadenine Example 549-Benzyl-8-hydroxy-2-(2-methoxycarbonylethyl)thioadenine Example 559-Benzyl-2-(2-ethoxycarbonylethyl)thio-8-hydroxyadenine Example 569-Benzyl-2-(3-ethoxycarbonylpropyl)thio-8-hydroxyadenine Example 579-Benzyl-2-(4-ethoxycarbonylbutyl)thio-8-hydroxyadenine Example 589-Benzyl-2-(ethoxycarbonylmethylcarbonylmethyl)thio-8-hydroxyadenineExample 59 9-Benzyl-2-(2-butyrolactino)thio-8-hydroxyadenine Example 608-Hydroxy-9-{(6-methyl-3-pyridyl)methyl}-2-{(2-oxo-1,3-dioxolan-4-yl)methylamino}adenine

8-Methoxy-9-{(6-methyl-3-pyridyl)methyl}-2-{(2-oxo-1,3-dioxolan-4-yl)methylamino}adenine(65 mg, 0.17 mmol) obtained by Reference example 19 was added toconcentrated hydrochloric acid, and the solution was stirred under icecooling for 15 hours. The solution was neutralized under ice coolingwith 40% sodium hydroxide solution, and the resulting white crystalswere purified by preparative thin-layer chromatography to give thecaptioned compound (18 mg, 0.049 mmol, yield: 29%) as a white solid.

Example 61 9-Benzyl-8-hydroxy-2-(2-methoxycarbonylethyl)adenine

After 9-benzyl-2-(2-carboxyethyl)-8-hydroxyadenine (100 mg, 0.32 mmol)obtained by Comparative example 15 was added to methanol (20 ml),sulfuric acid (2 ml) was added thereto, and the mixture was refluxed for4 hours under stirring. After being neutralized in an ice bath withsaturated sodium hydrogencarbonate solution, the solution was extractedwith chloroform. The organic layer was dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by columnchromatography (SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=100/1˜30/1) andthe obtained compound was washed with methanol to give the captionedcompound (74 mg, 0.23 mmol) as a white solid.

Example 62 9-Benzyl-2-ethoxycarbonylethyl-8-hydroxy adenine

The captioned compound was obtained in accordance with the method ofExample 61.

Example 63 9-Benzyl-8-hydroxy-2-(S-methylthiocarbonyl ethyladenine

To DMF (3 ml) were added 9-benzyl-2-(2-carboxyethyl)-8-hydroxyadenine(49 mg, 0.16 mmol) obtained by Comparative example 15,N-hydroxybenzotriazole (47 mg, 0.35 mmol), methanethiol, aqueous 15%sodium salt solution (161 mg, 0.34 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (66 mg, 0.34mmol), and the mixture was stirred at room temperature for 30 hours.After removing the solvent, the residue was poured into water and thesolution was extracted with chloroform. The organic layer was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=100/1˜30/1) and the obtained compound was washed withmethanol to give the captioned compound (17 mg, 0.050 mmol) as a whitesolid.

Example 64 9-Benzyl-8-hydroxy-2-methoxycarbonylmethoxyadenine

After sodium (0.30 g, 13.04 mmol) was dissolved in methanol (30 ml),thereto was added 9-benzyl-8-bromo-2-methoxycarbonylmethoxyadenine (0.10g, 0.25 mmol) obtained by Reference example 21, and the mixture wasrefluxed for 7 hours under stirring. After being allowed to cool, thesolution was neutralized with concentrated hydrochloric acid andconcentrated. After the residue was dissolved in methanol (30 ml),thereto was added sulfuric acid (2 ml) and the solution was stirred for7 hours. After being neutralized in an ice bath with saturated sodiumhydrogencarbonate solution, the solution was extracted with chloroform.The organic layer was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography (SiO₂ 20g, eluting solvent: CHCl₃/MeOH=100/1˜30/1) and the obtained compound waswashed with methanol to give the captioned compound (62 mg, 0.19 mmol)as a white solid.

Example 65 9-Benzyl-2-ethoxycarbonylmethoxy-8-hydroxyadenine

The captioned compound was obtained in accordance with the method ofExample 61.

Example 668-Hydroxy-2-methoxycarbonylethyl-9-{(6-methyl-3-pyridyl)methyl}adenine

8-Bromo-2-(2-methoxycarbonylethyl)-9-{(6-methyl-3-pyridyl)methyl}adenine(31 mg, 0.076 mmol) obtained by Reference example 24 was added toconcentrated hydrochloric acid (5 ml), and the mixture was stirred at100° C. for 4 hours. The solution was neutralized in an ice bath with 1Nsodium hydroxide solution, concentrated and the residue was dissolved inmethanol (70 ml). Thereto was added sulfuric acid (7 ml) and the mixturewas refluxed for 2 hours under stirring. After being neutralized in anice bath with saturated sodium hydrogencarbonate solution, the solutionwas extracted with chloroform. The organic layer was dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=50/1˜20/1), the obtained compound was washed with chloroformand dried in vacuo under heating to give the captioned compound (12 mg,0.035 mmol) as a white solid.

Example 678-Hydroxy-2-(2-methoxycarbonylethyl)-9-(4-methoxycarbonylmethylbenzyl)adenine

The captioned compound was obtained in accordance with the method ofExample 66.

Example 68 2-Butoxy-8-hydroxy-9-(4-ethoxycarbonylmethylbenzyl)adenine

The captioned compound was obtained in accordance with the method ofExample 61.

Example 692-Butoxy-8-hydroxy-9-{3-(2,2,2-trifluoroethoxycarbonyl)methylbenzyl}adenine

To DMF (3 ml) were added2-butoxy-9-(4-carboxylmethylbenzyl)-8-methoxyadenine (40 mg, 0.10 mmol)obtained in accordance with the method of Reference example 5,N-hydroxybenzotriazole (31 mg, 0.23 mmol), 2,2,2-trifluoroethanol (23mg, 0.23 mmol), diisopropylethylamine (59 mg, 0.46 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23mmol), and the mixture was stirred at room temperature for 17 hours.After removing the solvent, the residue was poured into water and thesolution was extracted with chloroform. The organic layer was dried overanhydrous magnesium sulfate, concentrated and the residue was purifiedby column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=200/1˜100/1). The resulting residue was added to THF (5.5 ml)and thereto was added concentrated hydrochloric acid (0.5 ml). Themixture was stirred at room temperature for 1 hour and neutralized withsaturated sodium hydrogencarbonate solution. The mixture was extractedwith chloroform. The organic layer was dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by columnchromatography (SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=200/1˜40/1) andthe obtained compound was washed with methanol to give the captionedcompound (10 mg, 0.022 mmol) as a white solid.

The compounds of Examples 70˜71 below were obtained in accordance withthe method of Example 69.

Example 702-Butoxy-8-hydroxy-9-{3-(2-fluoroethoxycarbonyl)methylbenzyl}adenineExample 712-Butoxy-8-hydroxy-9-{4-(2-hydroxyethoxycarbonyl)methylbenzyl}adenineExample 722-Butoxy-8-hydroxy-9-{4-(2-dimethylaminoethoxycarbonyl)methylbenzyl}adeninehydrochloride

2-Butoxy-9-(4-carboxylmethylbenzyl)-8-methoxyadenine (84 mg, 0.22 mmol)and potassium carbonate (133 mg, 0.96 mmol) were added to DMF (4 ml),and thereto was added 2-(dimethylamino)ethyl chloride hydrochloride (94mg, 0.65 mmol). The mixture was stirred at room temperature for 16hours. After removing the solvent, the residue was poured into water andextracted with chloroform. The organic layer was washed with saturatedbrine, dried over anhydrous magnesium sulfate, concentrated and purifiedby column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=100/1˜30/1). The resulting residue was added to THF (5.5 ml),and thereto was added concentrated hydrochloric acid (0.5 ml). Themixture was stirred at room temperature for 1 hour. The solution wasneutralized with sodium hydrogencarbonate solution, extracted withchloroform. The organic layer was dried over anhydrous magnesiumsulfate, concentrated and the residue was purified by columnchromatography (SiO₂ 20 g, eluting solvent: CHCl₃/MeOH=200/1˜40/1). Theresulting residue was dissolved into THF (3 ml) and thereto was addedconcentrated hydrochloric acid (5.5 μl). The mixture was stirred at roomtemperature for 30 minutes. The precipitated solid was filtered anddried in vacuo under heating to give the captioned compound (16 mg,0.033 mmol) as a white solid.

Example 732-Butoxy-8-hydroxy-9-{4-(2-morpholinoethoxycarbonyl)methylbenzyl}adenine

The captioned compound was obtained in accordance with the method ofExample 72.

Example 742-Butoxy-8-hydroxy-9-{4-(S-methylthiocarbonyl)methylbenzyl}adenine

The captioned compound was obtained in accordance with the method ofExample 63.

The compounds of Examples 75˜79 below were obtained in accordance withthe method of Example 69.

Example 752-Butoxy-9-{4-(S-ethylthiocarbonyl)methylbenzyl}-8-hydroxyadenineExample 76 2-Butoxy-8-hydroxy-9-(4-carbamoylmethylbenzyl)adenine Example77 2-Butoxy-8-hydroxy-9-(4-methylcarbamoylmethylbenzyl)adenine Example78 2-Butoxy-8-hydroxy-9-(4-dimethylcarbamoylmethylbenzyl)adenine Example79 2-Butoxy-8-hydroxy-9-(4-morpholinomethylbenzyl)adenine Example 802-Butoxy-9-(3-ethoxycarbonylmethylbenzyl)-8-hydroxyadenine

The captioned compound was obtained in accordance with the method ofExample 61.

Example 81 2-Butoxy-8-hydroxy-9-(5-methoxycarbonylmethylfurfuryl)adenine

2-Butoxy-9-(5-cyanomethylfurfuryl)-8-hydroxyadenine (29 mg, 0.085 mmol)obtained by Reference example 26 was added to a mixed solvent of 4Nsodium hydroxide solution (3 ml) and methanol (3 ml), and the mixturewas refluxed for 4 hours. The solution was neutralized in an ice bathwith concentrated hydrochloric acid. After removing the solvent invacuo, the residue and sulfuric acid (3 ml) were added to methanol (30ml). The mixture was refluxed for 2 hours under stirring. The solutionwas neutralized in an ice bath with saturated sodium hydrogencarbonatesolution, and extracted with chloroform. The combined organic layer wasdried over anhydrous magnesium sulfate and concentrated. The residue waspurified by column chromatography (SiO₂ 20 g, eluting solvent:CHCl₃/MeOH=70/1˜40/1), and the obtained compound was washed withmethanol and dried in vacuo under heating to give the captioned compound(16 mg, 0.091 mmol) as a white solid.

Example 822-Butoxy-8-hydroxy-9-{(6-S-methylthiocarbonyl-3-pyridyl)methyl}adenine

The captioned compound was obtained in accordance with the method ofExample 63.

Example 83 2-Butoxy-9-{(6-carbamoyl-3-pyridyl)methyl}-8-hydroxyadenine

The captioned compound was obtained in accordance with the method ofExample 69.

Example 84 2-Butoxy-8-hydroxy-9-(3-methoxycarbonylethylbenzyl)adenine

2-Butoxy-9-(3-methoxycarbonylethylbenzyl)adenine was obtained inaccordance with the method of Example 81. And then the captionedcompound was obtained in accordance with the method of Example 1.

Example 85 2-Butoxy-8-hydroxy-9-(4-methoxycarbonylethylbenzyl)adenine

The captioned compound was obtained in accordance with the method ofExample 84.

Example 86 2-Butoxy-9-(4-ethoxycarbonylethylbenzyl)-8-hydroxyadenine

The captioned compound was obtained in accordance with the method ofExample 61.

The compounds of Examples 87˜89 below were obtained in accordance withthe method of Example 1.

Example 872-Butoxy-8-hydroxy-9-{6-(4-methoxycarbonyl-1-piperidyl)-3-pyridylmethyl}adenineExample 882-Butoxy-8-hydroxy-9-{6-(3-methoxycarbonyl-1-piperidyl)-3-pyridylmethyl}adenineExample 892-Butoxy-8-hydroxy-9-{(6-methoxycarbonylmethoxy-2-naphthyl)methyl}adenineExample 90 2-Butoxy-9-(3,4-dimethoxycarbonylbenzyl)-8-hydroxyadenine

Staring from 2-butoxy-9-(3,4-dimethoxycarbonylbenzyl)adenine obtained byReference example 28, the captioned compound was obtained in accordancewith the method of Example 1.

Example 91 2-Butoxy-9-(3,5-dimethoxycarbonylbenzyl)-8-hydroxyadenine

The captioned compound was obtained in accordance with the method ofExample 90.

Example 922-Butoxy-8-hydroxy-9-{(6-methoxycarbonylmethyl-3-pyridyl)methyl}adenine

The captioned compound was obtained in accordance with the method ofExample 81.

Example 932-Butoxy-9-{6-(γ-butyrolactonyl)thio-3-pyridyl}methyl}-8-hydroxyadenine

Starting from2-butoxy-9-{6-(γ-butyrolactonyl)thio-3-pyridyl}methyl)adenine obtainedby Reference example 31, the captioned compound was obtained inaccordance with the method of Example 1.

Example 94 2-Butoxy-9-{4-(γ-butyrolactonyloxy)benzyl}-8-hydroxyadenine

Starting from 8-bromo-2-butoxy-9-{4-(γ-butyrolactonyloxy)benzyl}adenineobtained by Reference example 32, the captioned compound was obtained inaccordance with the method of Example 1.

Example 952-Butoxy-9-{4-(1-hydroxy-3-methoxycarbonylpropoxy)benzyl}-8-hydroxyadenine

The captioned compound was obtained in accordance with the method ofExample 1.

Example 968-Hydroxy-9-(3-methoxycarbonylmethylbenzyl)-2-(2-methoxyethoxy)adenine

9-(3-Carboxymethylbenzyl)-8-hydroxy-2-(2-methoxyethoxy)adenine (81 mg,0.22 mmol) obtained by Comparative example 27 was dissolved in methanol(3 ml), and thereto was added concentrated sulfuric acid (0.11 g, 1.10mmol). The mixture was refluxed for 20 minutes. The solution wasneutralized with saturated sodium hydrogencarbonate solution, extractedwith chloroform, dried over anhydrous magnesium sulfate andconcentrated. The residue was washed with diethyl ether to give thecaptioned compound (33 mg, yield 39%) as a white solid.

Example 97 2-Butylamino-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine

The captioned compound was obtained in accordance with the method ofExample 96.

Example 98 2-Chloro-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine

8-Bromo-2-chloro-9-(3-methoxycarbonylmethylbenzyl)adenine (1.78 g, 4.34mmol) obtained by Reference example 39 was suspended in the mixedsolvent of 1N sodium hydroxide solution (150 ml) and methanol (150 ml),and the mixture was stirred at 100° C. for 30 minutes. The residue wasneutralized with 12N hydrochloric acid. After removing the solvent, tothe residue were added methanol (50 ml) and concentrated sulfuric acid(2.45 g, 25.0 mmol) and the mixture was refluxed for 1 hour underheating. The solution was neutralized with saturated sodiumhydrogencarbonate solution and extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate, concentrated and theresidue was purified by column chromatography (SiO₂ 90.0 g, elutingsolvent: CHCl₃/MeOH=100/0˜50/1) to give the captioned compound (0.84 g,2.41 mmol, yield: 56%) as a white solid.

Example 998-Hydroxy-2-(2-hydroxyethylthio)-9-(3-methoxycarbonylmethylbenzyl)adenine

Sodium (67 mg, 2.90 mmol) was dissolved in 2-mercapt ethanol (2.5 ml)and thereto was added2-chloro-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine (100 mg,0.29 mmol) obtained by Example 98. The mixture was stirred at 120° C.for 4 hours and then neutralized with 12N hydrochloric acid. Afterremoving the solvent, to the residue were added methanol (3.0 ml) andconcentrated sulfuric acid (0.14 g, 1.43 mmol), and the mixture wasrefluxed for 30 minutes. The solution was neutralized with saturatedsodium hydrogencarbonate solution and extracted with chloroform. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated. To the residue was added water, the mixture was filteredand washed with water to give the captioned compound (55 mg, 0.14 mmol,yield: 49%) as a white solid.

The compounds of Examples 100˜102 below were obtained in accordance withthe method of Example 1.

Example 1002-Butoxy-8-hydroxy-9-[4-(1-methoxycarbonylethyl)benzyl]adenine Example101 2-Butoxy-8-hydroxy-9-[3-(2-methoxycarbonyl-2-propyl)benzyl]adenineExample 102 2-Butoxy-8-hydroxy-9-(4-methoxycarbonylphenethyl)adenine

The compounds of Examples 103˜106 were obtained in accordance with themethod of Example 40.

Example 103 9-Benzyl-8-hydroxy-2-[(3-methoxycarbonylbenzyl)thio]adenineExample 104 9-Benzyl-8-hydroxy-2-[(4-methoxycarbonylbenzyl)thio]adenineExample 1059-Benzyl-8-hydroxy-2-[(3-methoxycarbonylmethylbenzyl)thio]adenineExample 1069-Benzyl-8-hydroxy-2-[(4-methoxycarbonylmethylbenzyl)thio]adenine

The compounds of Examples 107˜109 below were obtained in accordance withthe method of Example 29.

Example 107 9-Benzyl-2-butoxycarbonylmethyl-8-hydroxyadenine Example 1089-Benzyl-8-hydroxy-2-(isopropoxycarbonylmethyl)adenine Example 1099-Benzyl-2-(2-fluoroethoxycarbonyl)methyl-8-hydroxyadenine Example 1109-Benzyl-8-hydroxy-2-(morpholinocarbonylmethyl)adenine

9-Benzyl-2-carboxymethyl-8-hydroxyadenine (15 mg, 0.050 mmol) obtainedby Comparative example 8, N-hydroxybenzotriazole (12 mg, 0.075 mmol),morpholine (7 mg, 0.075 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15 mg,0.075 mmol) were added to dichloromethane (10 ml), and the mixture wasstirred at room temperature for 5 hours. After removing the solvent, theresidue was poured into water and extracted with chloroform. The organiclayer was dried over anhydrous magnesium sulfate, concentrated and theresidue was purified by column chromatography (SiO₂ 20 g, elutingsolvent: CHCl₃/MeOH=100/3˜20/1) to give the captioned compound (8 mg,yield: 43%) as a white solid.

The compounds of Examples 111˜115 below were obtained in accordance withthe method of Example 1.

Example 1112-Butoxy-8-hydroxy-9-[(2-methoxycarbonylmethyl)benzyl]adenine

(108 mg, 0.28 mmol)

Example 1122-Butoxy-8-hydroxy-9-[(4-fluoro-3-methoxycarbonyl)benzyl]adenine)

(170 mg, 0.44 mmol)

Example 1132-Butoxy-8-hydroxy-9-[(4-methoxy-3-methoxycarbonyl)benzyl]adenine

(369 mg, 0.92 mmol)

Example 1142-Butoxy-8-hydroxy-9-[4-(2-methoxycarbonyl-2-methylethyl)benzyl]adenine

(305 mg, 0.74 mmol)

Example 1152-Butoxy-8-hydroxy-9-[3-((2R,S)-methoxycarbonylethyl)benzyl]adenine

(287 mg, 0.72 mmol)

Example 116 2-Butoxy-8-hydroxy-9-{3-[methoxy(oxo)acetyl]benzyl}adenine

2-Butoxy-8-hydroxy-9-[3-(oxocarboxymethyl)benzyl]adenine (0.13 g, 0.34mmol) obtained by Comparative example 43 was dissolved in methanol (3.5ml), and thereto was added at 0° C. concentrated sulfuric acid (0.2 ml).The solution was stirred at room temperature for 2 hours and neutralizedwith saturated sodium hydrogencarbonate solution. After adding water,the precipitated solid was filtered, purified by column chromatography(SiO₂ 5.0 g, eluting solvent: CHCl₃/MeOH=10/1) and the obtained compoundwas washed with water to give the captioned compound (0.086 g, 0.22mmol, yield: 64%) as a white solid.

Example 1172-Butoxy-8-hydroxy-9-{3-[(1-hydroxy-2-methoxy)acetyl]benzyl}adenine

The captioned compound was obtained in accordance with the method ofExample 116, Yield: 82%.

The compounds of Examples 118˜119 below were obtained in accordance withthe method of Example 1.

Example 1182-Butoxy-8-hydroxy-9-{(2-methoxycarbonyl-4-pyridyl)methyl}adenineExample 1192-Butoxy-8-hydroxy-9-{(5-methoxycarbonyl-2-thienyl)methyl}adenine

The compounds of Examples 120˜121 below were obtained in accordance withthe method of Example 81.

Example 1209-{3,5-Bis(methoxycarbonylmethyl)benzyl}-2-butoxy-8-hydroxyadenineExample 1212-Butoxy-8-hydroxy-9-{(5-methoxycarbonylmethyl-3-pyridyl)methyl}adenineExample 122 Interferon Inducing Activity on Cells of Mouse Spleen (InVitro)

By using a spleen extracted from a C3H/HeJ mouse (male; 8-10 weeks old),a suspension of spleen cells (2×10⁶ cells/ml) was prepared in MEM brothcontaining 5% FBS. To each well of a 24-well microplate was poured thesuspension (0.5 ml). To each well was added 0.5 ml of the test compound(containing 0.2% DMSO) diluted with the same broth, and the microplatewas incubated at 37° C. for 24 hours in a 5% CO₂ incubator. The culturebroth was aseptically filtered by a filter (0.2 micrometer) to give asupernatant. The interferon activity in the supernatant wasquantitatively measured by the bioassay method described in J. A.Armstrong, Methods in Enzymology 78, 381-7. Namely, after mousefibroblast L929 (1×10⁴ cells/50 μl) were cultured in a 96-well cultureplate for 24 hours, thereto was added 50 μl of the diluted culturesupernatant and the mixture was further cultivated for 24 hours. Andthen 100 μl of vesicular stomatitis virus were added to each well. Fortyfour hours after the virus infection, the effect of the celldenaturation was confirmed by the crystal violet stain. The quantitativeanalysis was carried out by dissolving the pigment in 2% sodiumdeoxycholate solution and measuring absorbance at 595 nm. In Table 1,interferon inducting activity on each compound (Minimum effectiveconcentration) was shown.

TABLE 1 Minimum effective Compound concentration (μM) Example 1 <0.001Example 6 <0.001 Example 7 <0.001 Example 15 0.003 Example 16 0.003Example 19 <0.001 Example 20 0.003 Example 21 0.003 Example 24 <0.001Example 25 0.003 Example 29 0.01 Example 30 0.01 Example 32 0.01 Example33 0.1 Example 34 0.1 Example 38 0.01 Example 40 0.01 Example 48 0.3Example 50 0.1 Example 51 0.1 Example 53 0.1 Example 54 0.1 Example 580.1 Example 59 0.1 Comparative example 1 0.003 Comparative example 3 0.1Comparative example 5 0.1 Comparative example 6 0.03 Comparative example8 10 Comparative example 10 1 Comparative example 11 0.1 Comparativeexample 12 10 Comparative example 13 10

Example 123 Interferon Inducing Activity on Cells of Rat Spleen (InVitro)

By using a spleen extracted from a SD rat (male; 8-10 weeks old), asuspension of spleen cells (2×10⁶ cells/ml) was prepared in MEM brothnot containing any blood. To each well of a 24-well microplate waspoured the suspension (0.5 ml). To each well was added 0.5 ml of thetest compound (containing 0.2% DMSO) diluted with the same broth, andthe microplate was incubated at 37° C. for 24 hours in a 5% CO₂incubator. The culture broth was aseptically filtered by a filter (0.2micrometer) to give a supernatant. The interferon activity in thesupernatant was quantitatively measured by the bioassay method describedin J. A. Armstrong, Methods in Enzymology 78, 381-7. Namely, after mousefibroblast L929 (1×10⁴ cells/50 μl) were cultured in 96-wells cultureplate for 24 hours, thereto was added 50 μl of diluted culturesupernatant and the mixture was further cultivated for 24 hours. Andthen 100 μl of vesicular stomatitis virus were added. Forty four hoursafter the virus infection, the effect of the cell denaturation wasconfirmed by crystal violet stain. The quantitative analysis was carriedout by extracting the pigment with 50% ethanol and PBS solution andmeasuring absorbance at 540 nm. In Table 2, interferon inductingactivity on each compound (Minimum effective concentration) was shown.

TABLE 2 Minimum effective Compound concentration (nM) Example 1 0.3Example 2 1 Example 15 1 Example 17 1 Example 19 0.3 Example 20 0.1Example 21 1 Example 23 100 Example 24 0.3 Example 29 10 Example 30 10Example 40 10 Example 54 10 Example 61 3 Example 62 30 Example 63 100Example 64 3 Example 65 30 Example 66 1 Example 67 1 Example 68 0.3Example 70 1 Example 71 0.3 Example 73 0.3 Example 74 1 Example 75 3Example 76 0.1 Example 77 0.3 Example 78 0.03 Example 79 0.3 Example 801 Example 81 1 Example 82 100 Example 83 0.3 Example 84 10 Example 87 1Example 90 0.3 Example 93 3 Example 95 1 Example 96 3 Example 100 0.3Example 103 10 Example 104 100 Example 105 300 Example 106 100 Example107 100 Example 108 30 Example 109 30 Example 110 100 Comparative ex. 110 Comparative ex. 3 10 Comparative ex. 5 10 Comparative ex. 6 10Comparative ex. 8 3000 Comparative ex. 12 300 Comparative ex. 13 300Comparative ex. 15 1000 Comparative ex. 16 1000 Comparative ex. 17 300Comparative ex. 18 3000 Comparative ex. 19 30 Comparative ex. 20 30Comparative ex. 21 3 Comparative ex. 23 100 Comparative ex. 26 3Comparative ex. 27 300 Comparative ex. 31 30 Comparative ex. 34 300Comparative ex. 35 1000 Comparative ex. 36 3000 Comparative ex. 37 1000

Example 124 Metabolic Stability Test on Serum

Plasma was prepared from fresh blood of a SD rat (male; 8-10 weeks old)and thereto was added the test compound to give the final concentration10 μM (containing 1% DMSO) After the mixture was metabolized with aplasma esterase at 37° C. for 15 minutes, the test-compound wasextracted with ethyl acetate, and was quantitatively analyzed by reversephase HPLC. The metabolic stability of the test compound was presentedby the residual amount (%) per the concentration of pre-metabolization.The result was shown in Table 3.

TABLE 3 Compound Residual rate (%) Example 1 32  Example 2 5 Example 320  Example 4 23  Example 5 18  Example 6 14  Example 7 1 Example 8 16 Example 9 1 Example 11 13  Example 12 29  Example 13 10  Example 15 0Example 16 0 Example 17 0 Example 18 0 Example 19 1 Example 20 0 Example21  0* Example 22 0 Example 24 7 Example 25 16  Example 27 0 Example 290 Example 30 0 Example 31 0 Example 32 0 Example 34 11  Example 37 0Example 38 2 Example 40 0 Example 41 0 Example 42 0 Example 43 0 Example44 0 Example 45 0 Example 46 0 Example 47 0 Example 48 0 Example 49 0Example 53 0 Example 54 0 Example 55 0 Example 56 0 Example 58 0 Example59 0 Example 61  0* Example 62  0* Example 64  0* Example 65  0* Example68  0* Example 70  0* Example 71  0* Example 73  4* Example 74  0*Example 75  0* Example 80  0* Example 103  6* *The concentration of thetest compound: 1 μM

Example 125 Metabolic Stability on River S9 of Rat

The reaction on river S9 of a rat was carried out on a 96-well plate byusing a robot for screening by Tecan Company. S9 solution was preparedby adding to 10 ml of liver S9 of a rat, 20 ml of 250 mM Kpi (pH 7.4)and 20 ml of deionized water. Cofactor solution was prepared bydissolving NADPH (220 mg) in deionized water (40.5 ml) to give finally a6 mM solution. IS (Internal Standard) solution was prepared by adding300 μL of IS solution (1 mM DMSO solution) to 30 ml of acetonitrilesolution (100 times dilution). The test compound (1 μM DMSO solution)was dissolved in an incubator at 37° C., 35 μL of it was poured intoeach well of a 96-well plate (24 samples/plate and then, plates (asample plate, a 96 well-plate for dilution, deep well plates forreaction and recovering, a plate for extraction of the solid phase) andthe test samples (S9 solution, Cofactor solution, IS (Internal Standard)solution, Stop solution, acetonitrile for elution) were set to thespecified position in the booth of the robot. The reaction started (theconcentration of the test compound was 1 μM) and the mixture wasincubated at 37° C. under stirring. The solid phase was extracted and atthe same time the internal standard for analysis was added. To therecovered sample (200 μL/well) was added 50 μL of acetonitrile per eachwell and to 2 plates of FALCON Deep well were poured 100 μL of thesolution per well. By subjecting to the LC/MS analysis, the chromatogramof the test sample and the internal standard were described and the peakarea was calculated. And then, the stability (residual rate afterreaction) was calculated by the internal standard method. The result wasshown in Table 4.

TABLE 4 Compound Residual rate (%) Example 1 7 Example 2 11  Example 319  Example 4 25  Example 8 1 Example 14 22  Example 15 11  Example 16 0Example 17 28  Example 19 0 Example 20 0 Example 21 26  Example 22 31 Example 30 4 Example 31 3 Example 33  2* Example 34  1* Example 41  2*Example 42 3 Example 43 2 Example 44 0 Example 45  8* Example 46 0Example 47 0 Example 48 0 Example 49 0 Example 50 7 Example 51 0 Example52 24  Example 53 2 Example 55  4* Example 56 1 Example 57 3 Example 597 Example 61 0 Example 62 0 Example 63 0 Example 64 2 Example 66 0Example 67 0 Example 68 13  Example 70 16  Example 71 0 Example 72 4Example 73 0 Example 74 7 Example 79 17  Example 80 0 Example 81 2Example 82 2 Example 84 1 Example 86 18  Example 90 3 Example 94 2Example 95 4 Example 96 0 Example 100 1 Example 103 7 Example 105 1Example 106 3 Example 107 3 Example 108 3 Example 109 0 *Theconcentration of the test compound: 10 μM

Example 126 The Measurement of the Amount of Leucocytes and Cytokines inBronchoalveolar Lavege Fluid (BALF) on an Asthma Modeled Mouse

C57BL/6 mouse was immunized by dermally administering denaturedovalbumin by heating (40 mg). Fourteen days later after the firstimmunization, ovalbumin (100 μg) was nasally busted. Twenty one dayslater after the first immunization, the solution (1 ml/kg) prepared bysuspending the test compound (10 mg/kg) in physiological saline wasnasally administered (10 μl/10 g/body weight). After 2 hours ovalbumin(100 μg) was nasally challenged. After 18 hours, bronchoalveolar lavegefluid (BALF) was collected, and the total number of leucocytes in BALFand fractioned leukocyte in the cytospin sample were measured. By ELISAmethod, IL-4 and IL-5 in the supernatant were measured. The number ofleucocytes (inhibition %) was shown in Table 5 and the productioninhibition activity of IL-4 and IL-5 (inhibition % to control) was shownin Table 6.

TABLE 5 Number of Compound total leukocyte Acidophile Netrophile Example15 84 101 −92 Beclometasone 92 89 90 dipropionate

TABLE 6 Compound IL-4 IL-5 Example 15 80 75 Beclometasone dipropionate97 100

Example 127 Anti HSV Activity of Antedrug for Herpes Virus (HSV)Infected Vagina of Modeled Rat

On the back of a BALB/c female mouse (6 weeks old: Nippon SLC) 3 mg ofDepo-Provera/mouse (Registered Trade Mark) was dermally administered andthe mice were fed for 6 days. By doing this the sexual cycle was tunedand the sensitivity between mice to herpes virus was balanced. The slimeof mouse vagina was removed by a cotton swab for baby, and the ointment(20 mg) containing 0.5% of compound of Example 20 or the ointment (10mg) containing 5% of compound of Example 20 was spread to the vagina(corresponding 0.1 mg and 0.5 mg per mouse of the compound of Example).As a control, the placebo ointment not containing the compound wasspread as well. As the ointment, the base consisting of 80% Vaseline and20% liquid paraffin were used. On the next day, the slime of mousevagina was removed by a cotton swab for baby and then, 2×10⁴ pfu type 2herpes virus (HSV-2)(10 μl/mouse) was administered to the vagina bypipette. After infection the death or survival of the mice was observed.

The survived rate of mice 9 days later after virus-infection was shownin FIG. 1. The groups spread by the ointments containing 0.5% and 5% ofthe compound of Example 20, respectively showed clearly higher survivedrate comparing with a control group, and the dosage dependency wasobserved. Furthermore, though the survived rate of the control group was0%, in the group of 5% ointment its survived rate was 100% and thelatter showed clearly anti-viral effect.

Example 128

The aerosol preparation (1 g) containing the following ingredients areprepared.

Compound of Example 15: 0.641 mg (0.06%)

Ethanol: 26.816 mg (2.68%)

1,1,1,2-Tetrafuruoroethane: 972.543 mg (97.25%)

Example 129

The aerosol preparation (1 g) containing the following ingredients areprepared.

Compound of Example 22: 0.641 mg (0.06%)

Ethanol: 26.816 mg (2.68%)

1,1,1,2-Tetrafuruoroethane: 972.543 mg (97.25%)

Example 130

The aerosol preparation (1 g) containing the following ingredients areprepared.

Compound of Example 41: 0.641 mg (0.06%)

Ethanol: 26.816 mg (2.68%)

1,1,1,2-Tetrafuruoroethane: 972.543 mg (97.25%)

Example 131

The aerosol preparation (1 g) containing the following ingredients areprepared.

Compound of Example 19: 0.641 mg (0.06%)

Ethanol: 26.816 mg (2.68%)

1,1,1,2-Tetrafuruoroethane: 972.543 mg (97.25%)

Example 132

The aerosol preparation (1 g) containing the following ingredients areprepared.

Compound of Example 67: 0.641 mg (0.06%)

Ethanol: 26.816 mg (2.68%)

1,1,1,2-Tetrafuruoroethane: 972.543 mg (97.25%)

Comparative Example 1 2-Butoxy-8-hydroxy-9-(3-carboxy benzyl)adenine

2-Butoxy-8-hydroxy-9-(3-methoxycarbonylbenzyl)adenine (0.10 g, 0.27mmol) obtained by Example 1 was added to 5% sodium hydroxide solution(10 ml) and the solution was stirred at room temperature for 2 hours.After the reaction mixture was neutralized with concentratedhydrochloric acid, the resulting solid was filtered and washed withmethanol to give the captioned compound (0.06 g, 0.17 mmol, yield: 61%)as a white solid.

The compounds of Comparative examples 3-8 below were obtained inaccordance with the method of Comparative example 1.

Comparative Example 3 2-Butoxy-8-hydroxy-9-(5-carboxyfurfuryl)adenineComparative Example 52-Butoxy-8-hydroxy-9-(3-carboxymethylbenzyl)adenine Comparative Example6 2-Butoxy-8-hydroxy-9-(4-carboxymethylbenzyl)adenine ComparativeExample 8 9-Benzyl-2-carboxymethyl-8-hydroxyadenine Comparative Example9 9-Benzyl-8-hydroxy-2-(2-hydroxyethylamino)adenine

9-Benzyl-8-bromo-2-(2-hydroxyethylamino)adenine 600 mg (1.7 mmol)obtained by Reference example 8 in 6N hydrochloric acid (3 ml) wasstirred at 100° C. for 8 hours. After the reaction mixture wasneutralized under ice cooling with 40% sodium hydroxide solution, theresulting solid was filtered and washed with water to give the captionedcompound (190 mg, 0.63 mmol, yield: 38%) as a white solid.

Comparative Example 108-Hydroxy-2-(2-hydroxyethylamino)-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was obtained in accordance with the method ofComparative example 9.

Comparative Example 118-Hydroxy-2-(2-hydroxyethoxy)-9-{(6-methyl-3-pyridyl)methyl}adenine

2-Hydroxyethoxy-8-methoxy-9-[(6-methyl-3-pyridyl)methyl]adenine (640 mg,1.9 mmol) obtained by Reference example 13 in concentrated hydrochloricacid (5 ml) was stirred at room temperature for 6 hours. After thereaction mixture was neutralized under ice cooling with 24% sodiumhydroxide solution, the resulting solid was filtered and washed withwater to give the captioned compound (440 mg, 1.4 mmol, yield: 73%) as awhite solid.

Comparative Example 12 9-Benzyl-8-hydroxy-2-(calboxylmethyl)thioadenine

To sodium hydroxide (500 mg) in methanol (5 ml) was added9-benzyl-8-hydroxy-2-(methoxycarbonylmethyl)thioprine (64 mg, 0.19mmol), and the mixture was refluxed for 2 hours. After the reactionmixture was neutralized with 2N hydrochloric acid, the resulting solidwas filtered and washed with water to give the captioned compound (32mg, yield: 52%) as a white solid.

Comparative Example 13 9-Benzyl-8-hydroxy-2-(2-calboxylethyl)thioadenine

The captioned compound was obtained in accordance with the method ofExample 40.

Comparative Example 142-(2,3-dihydroxypropylamino)-8-hydroxy-9-{(6-methyl-3-pyridyl)methyl}adenine

The captioned compound was obtained in accordance with the method ofComparative example 10.

Comparative Example 15 9-Benzyl-2-(2-carboxyethyl)-8-hydroxyadenine

To dimethyl malonate (493 mg, 3.73 mmol) in DMF (8 ml) was added in anice bath sodium hydride (75 mg, 3.13 mmol). Then the mixture was stirredat room temperature for 30 minutes. Thereto was added9-benzyl-2-chloromethyl-8-hydroxyadenine (0.10 g, 0.37 mmol), and themixture was stirred at room temperature for 21 hours. After removing thesolvent, the residue was poured into water, concentrated, andneutralized with hydrochloric acid. The resulting solid was filtered,washed with water and dried in vacuo under heating to give9-benzyl-2-(2,2-dimethoxycarbonylethyl)-8-hydroxyadenine (92 mg, 0.24mmol) as a white solid. Thus obtained9-benzyl-2-(2,2-dimethoxycarbonylethyl)-8-hydroxyadenine (79 mg, 0.20mmol) was added to a mixed solvent of concentrated hydrochloric acid (2ml) and 1,4-dioxane (6 ml), and the mixture was refluxed for 6 hours.After the reaction mixture was neutralized in an ice bath with saturatedsodium hydrogencarbonate solution, the resulting solid was filtered,washed with water and dried in vacuo under heating to give the captionedcompound (55 mg, 0.18 mmol) as a white solid.

Comparative Example 16 9-Benzyl-8-hydroxy-2-calboxylmethoxyadenine

The captioned compound was obtained in accordance with the method ofComparative example 1.

Comparative Example 172-(2-Carbonxylethyl)-8-hydroxy-9-{(6-methyl-3-pyridyl)methyl}adenine)hydrochloride

8-Hydroxy-2-(2-methoxycarbonylethyl)-9-{(6-methyl-3-pyridyl)methyl}adenine(9 mg, 0.026 mmol) obtained by Example 66 was added to concentratedhydrochloric acid (1 ml), and the solution was stirred at 100° C. for 1hour. After removing the solvent, the residue was dissolved in methanoland the solution was added to diisopropyl ether. The resulting solid wasfiltered and dried in vacuo under heating to give the captioned compound(7 mg, 0.019 mmol) as a white solid.

The compounds of Comparative examples 18˜26 below were obtained inaccordance with the method of Comparative example 1.

Comparative Example 182-(2-Carboxylethyl)-9-(4-carboxylmethylbenzyl)-8-hydroxyadenineComparative Example 192-Butoxy-9-(5-carboxylmethylfurfuryl)-8-hydroxyadenine ComparativeExample 20 2-Butoxy-9-(3-carboxylethylbenzyl-8-hydroxyadenineComparative Example 212-Butoxy-9-{6-(4-carboxyl-1-piperidyl)-3-pyridylmethyl-8-hydroxyadenineComparative Example 222-Butoxy-9-{6-(3-carboxyl-1-piperidyl)-3-pyridylmethyl-8-hydroxyadenineComparative Example 232-Butoxy-9-(3,4-dicarboxylbenzyl)-8-hydroxyadenine Comparative Example24 2-Butoxy-9-(3,5-dicarboxylbenzyl)-8-hydroxyadenine ComparativeExample 252-Butoxy-9-{(6-carboxylmethyl-3-pyridyl)methyl}-8-hydroxyadenineComparative Example 262-Butoxy-9-{6-(1-hydroxy-3-carboxylpropyl)thio-3-pyridyl}methyl}-8-hydroxyadenineComparative Example 279-(3-Carboxymethylbenzyl)-8-hydroxy-2-(2-methoxyethoxy)adenine

8-Bromo-9-(3-methoxycarbonylmethylbenzyl)-2-(2-methoxyethoxy)adenine(0.22 g, 0.50 mmol) obtained by Reference example 35 was suspended in amixed solvent of 1N sodium hydroxide solution (15 ml) and methanol (15ml), and the suspension was stirred at 100° C. for 2.5 hours. Afterremoving the solvent, 12N hydrochloric acid (10 ml) was added to thereaction mixture and the mixture was stirred at room temperature for 3.5hours. After the reaction mixture was neutralized with saturated sodiumhydrogencarbonate solution, the resulting solid was successively washedby water and methanol to give the captioned compound (0.14 g, 0.37 mmol,yield: 73%) as a pale red solid.

Comparative Example 282-Butylamino-9-(3-carboxymethylbenzyl)-8-hydroxyadenine

The captioned compound was obtained in accordance with the method ofComparative example 27.

Comparative Example 299-(3-Carboxymethylbenzyl)-2-chloro-8-hydroxyadenine

2-Chloro-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine (50 mg, 0.14mmol) obtained by Example 98 was dissolved in a mixed solvent of 1Nsodium hydroxide solution (5 ml) and methanol (5 ml), and the solutionwas stirred at 100° C. for 5 minutes. The solution was neutralized with12N hydrochloric acid and the solvent was removed. The residue was addedto water, the resulting solid was filtered and washed with water to givethe captioned compound (24 mg, 0.072 mmol, yield: 50%) as a pale redsolid.

Comparative Example 309-(3-Carboxymethylbenzyl)-8-hydroxy-2-(2-hydroxyethylthio)adenine

The captioned compound was obtained in accordance with the method ofComparative example 29.

The compounds of Comparative examples 31˜37 below were obtained inaccordance with the method of Comparative example 1.

Comparative Example 312-Butoxy-8-hydroxy-9-[4-(1-carboxyethyl)benzyl]adenine ComparativeExample 32 2-Butoxy-8-hydroxy-9-[3-(2-carboxy-2-propyl)benzyl]adenineComparative Example 33 2-Butoxy-8-hydroxy-9-(4-carboxyphenethyl)adenineComparative Example 349-Benzyl-8-hydroxy-2-[(3-carboxybenzyl)thio]adenine Comparative Example35 9-Benzyl-8-hydroxy-2-[(4-carboxybenzyl)thio]adenine ComparativeExample 36 9-Benzyl-8-hydroxy-2-[(3-carboxymethylbenzyl)thio]adenineComparative Example 379-Benzyl-8-hydroxy-2-[(4-carboxymethylbenzyl)thio]adenine

The structures and physical properties of the compounds of Referenceexamples, Examples and Comparative examples are shown below.

TABLE 7 Reference ex. Structure Yield 1

3.72 g 2

1.90 g 3

0.50 g 4

0.45 g 5

0.13 g 6

2.08 g

TABLE 8

Reference ex. —R^(2a) —R^(8a) ¹H-NMR 7 —NH(CH₂)₂OH —H (DMSO-d₆) δ 87.76(1H, s), 7.27 (5H, m), 6.66 (2H, brs), 6.08 (1H, t, J = 5.0 Hz), 5.13(2H, s), 4.62 (1H, t, J = 5.0 Hz), 3.46 (2H, q, J = 5.0 Hz), 2.46 (2H,q, J = 5.0 Hz). 8 —NH(CH₂)₂OH —Br (DMSO-d₆) δ 7.28 (5H, m), 6.92 (2H,brs), 6.30 (1H, t, J = 6.0 Hz), 5.17 (2H, s), 3.49 (2H, q, J = 6.0 Hz),3.31 (2H, q, J = 6.0 Hz). 15 —SH —H (DMSO-d₆) δ 12.10 (1H, brs), 10.06(1H, brs), 7.30 (5H, m), 6.74 (2H, brs), 4.85 (2H, s).

TABLE 9

Reference ex. —R^(2a) —R^(8a) ¹H-NMR 9 —NH(CH₂)₂OH —H (DMSO-d₆) δ 8.48(1H, s), 7.82 (1H, s), 7.63 (1H, d, J = 6.8 Hz), 7.21 (1H, d, J = 6.8Hz), 6.71 (2H, brs), 6.13 (1H, t, J = 5.6 Hz), 5.12 (2H, s), 4.67 (1H,t, J = 5.6 Hz), 3.50 (2H, q, J = 5.6 Hz), 3.30 (2H, q, J = 5.6 Hz), 2.42(3H, s). 10 —NH(CH₂)₂OH —Br (DMSO-d₆) δ 8.44 (1H, s), 7.54 (1H, d, J =6.8 Hz), 7.22 (1H, d, J = 6.8 Hz), 6.92 (2H, brs), 6.32 (1H, t, J = 5.6Hz), 5.16 (2H, s), 3.50 (2H, t, J = 5.6 Hz), 3.32 (2H, q, J = 5.6 Hz),2.43 (3H, s). 11 —(CH₂)₂OH —H (DMSO-d₆) δ 8.50 (1H, d, J = 1.6 Hz), 8.06(1H, s), 7.63 (1H, dd, J = 7.6, 1.6 Hz), 7.23 (2H, brs), 7.21 (1H, d, J= 7.6 Hz), 5.24 (2H, s), 4.82 (1H, t, J = 5.2 Hz), 4.22 (2H, t, J = 5.2Hz), 3.67 (2H, q, J = 5.2 Hz), 2.40 (3H, s). 12 —O(CH₂)₂OH —Br (DMSO-d₆)δ 12.02 (1H, brs), 8.53 (1H, d, J = 2.0 Hz), 7.69 (1H, dd, J = 4.0, 2.0Hz), 7.47 (2H, brs), 7.33 (1H, d, J = 4.0 Hz), 5.28 (2H, s), 4.23 (2H,t, J = 5.6 Hz), 3.67 (2H, t, J = 5.6 Hz), 2.48 (3H, s). 13 —O(CH₂)₂OH—OMe (DMSO-d₆) δ 8.41 (1H, d, J = 2.0 Hz), 7.53 (1H, dd, J = 8.0, 2.0Hz), 7.21 (1H, d, J = 8.0 Hz), 6.87 (2H, brs), 5.02 (2H, s), 4.80 (1H,t, J = 5.6 Hz), 4.19 (2H, t, J = 5.6 Hz), 4.05 (3H, s), 3.67 (2H, q, J =5.6 Hz), 2.41 (3H, s). 14 —O(CH₂)₂OCONMe₂ —OMe (DMSO-d₆) δ 8.54 (1H, d,J = 2.0 Hz), 7.58 (1H, dd, J = 8.0, 2.0 Hz), 7.09 (1H, d, J = 8.0 Hz),5.20 (2H, brs), 5.06 (2H, s), 4.54 (2H, m), 4.43 (2H, m), 4.11 (3H, s),2.90 (6H, d, J = 8.0 Hz), 2.52 (3H, s). 16 —NHCH₂CH(OH)CH₂OH —H(DMSO-d₆) δ 8.49 (1H, s), 7.83 (1H, s), 7.64 (1H, d, J = 8.0 Hz), 7.21(1H, d, J = 8.0 Hz), 6.76 (2H, brs), 6.08 (1H, t, J = 5.6 Hz), 5.16 (2H,s), 4.90 (1H, d, J = 4.8 Hz), 4.62 (1H, t, J = 6.0 Hz), 3.60 (1H, m),3.40 (3H, m), 3.20 (1H, m), 2.42 (3H, s). 17 —NHCH₂CH(OH)CH₂OH —Br(DMSO-d₆) δ 8.45(1H, s), 7.56 (1H, d, J = 7.2 Hz), 7.64 (1H, d, J = 7.2Hz), 7.02 (2H, brs), 6.27 (1H, t, J = 6.7 Hz), 5.16 (2H, s), 4.83 (1H,brs), 4.60 (1H, brs), 3.63 (1H, m), 3.40 (3H, m), 3.20 (1H, m), 2.42(3H, s). 18 —NHCH₂CH(OH)CH₂OH —OMe (DMSO-d₆) δ 8.40 (1H, d, J = 2.0 Hz),7.54 (1H, dd, J = 8.0, 2.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 6.44 (2H,brs), 5.94 (1H, t, J = 5.6 Hz), 4.95 (2H, s), 4.90 (1H, d, J = 4.4 Hz),4.60 (1H, t, J = 5.6 Hz), 4.00 (3H, s), 3.60 (1H, m), 3.39 (3H, m), 3.19(1H, m), 2.42 (3H, s). 19

—OMe ¹H NMR (DMSO-d₆) δ 8.39 (1H, d, J = 1.4 Hz), 7.53 (1H, dd, J = 8.0,1.4 Hz), 7.20 (1H, d, J = 8.0 Hz), 6.52 (1H, t, J = 5.6 Hz), 6.47 (2H,brs), 4.97 (2H, s), 4.93 (1H, m), 4.52 (1H, t, J = 8.4 Hz), 4.37 (1H,m), 4.01 (3H, s), 3.60 (1H, m), 3.50 (1H, m), 2.42 (3H, s).

TABLE 10 Reference ex. Structure Yield 20

0.12 g 21

0.10 g 22

0.23 g 23

 358 m g 24

  31 mg 25

  50 mg 26

  31 mg 27

2.05 g 28

 775 mg 29

  78 mg 30

0.98 g 31

0.31 g 32

0.19 g 33

3.06 g

TABLE 11

Reference ex. —R^(2a) —R^(8a) ¹H-NMR 34 —O(CH₂)₂OMe —H (DMSO-d₆) δ 8.04(1H, s), 7.29 (1H, dd, J = 7.6 Hz, 7.6 Hz), 7.24-7.17 (5H, m), 5.24 (2H,s), 4.32 (2H, t, J = 4.8 Hz), 3.65 (2H, s), 3.61 (2H, t, J = 4.8 Hz),3.58 (3H, s), 3.28 (3H, s). 35 —O(CH₂)₂OMe —Br (CDC1₃) δ 7.29-7.20 (4H,m), 6.44 (2H, brs), 5.28 (2H, s), 4.49 (2H, t, J = 4.4 Hz), 3.75 (2H, t,J = 4.4 Hz), 3.67 (3H, s), 3.60 (2H, s), 3.43 (3H, s). 36 —NH-Butyl —H(DMSO-d₆) δ 7.44 (1H, s), 7.31-7.18 (4H, m), 5.66 (2H, brs), 5.19 (2H,s), 4.97 (1H, brs), 3.66 (3H, s), 3.60 (2H, s), 3.40 (2H, dt, J = 6.0Hz, 7.2 Hz), 1.56 (2H, tt, J = 7.6 Hz, 7.2 Hz), 1.39 (2H, tq, J = 7.6Hz, 7.2 Hz), 0.93 (3H, t, J = 7.2 Hz). 37 —NH-Butyl —Br (CDC1₃) δ7.29-7.19 (4H, m), 5.75 (2H, brs), 5.20 (2H, s), 5.07 (1H, brs), 3.67(3H, s), 3.60 (2H, s), 3.39 (2H, dt, J = 6.8 Hz, 6.8 Hz), 1.56 (2H, tt,J = 6.8 Hz, 7.6 Hz), 1.38 (2H, tq, J = 7.6 Hz, 7.2 Hz), 0.92 (3H, t, J =7.2 Hz). 38 —Cl —H (DMSO-d₆) δ 8.24 (1H, s), 7.80 (2H, brs), 7.31 (1H,dd, J = 7.6 Hz, 7.6 Hz), 7.19 (1H, d, 7.6 Hz), 7.18 (1H, s), 7.14 (1H,d, 7.6 Hz), 5.32 (2H, s), 3.66 (2H, s), 3.59 (3H, s). 39 —Cl —Br (CDC1₃)δ 7.32 (1H, dd, J = 8.0 Hz, 7.6 Hz), 7.26-7.19 (3H, m), 5.72 (2H, brs),5.34 (2H, s), 3.70 (3H, s), 3.61 (2H, s).

TABLE 12 Reference ex. Structure Yield 40

4.71 g 41

4.92 g 42

4.62 g 43

4.79 g 44

4.36 g 45

4.42 g 46

3.07 g 47

3.43 g 48

2.26 g 49

2.97 g 50

2.90 g 51

2.80 g 52

2.84 g 53

2.48 g 54

2.16 g 55

3.75 g

TABLE 13 Reference ex. Structure ¹H-NMR (ppm) 56

(CDC1₃) δ 7.64 (1H, s), 7.60-7.51 (1H, m), 7.42- 7.34 (2H, m), 4.50 (2H,s), 3.74 (3H, s), 3.27 (6H, s). 57

¹H NMR (CDCl₃) δ 7.65 (1H, s), 7.61 (1H, s), 7.53 (1H, d, J = 7.7 Hz),7.35 (1H, dd, J = 7.7 Hz, 7.7 Hz), 7.26 (1H, d, J = 7.7 Hz), 6.41 (2H,brs), 5.29 (2H, s), 4.34 (2H, t, J = 6.6 Hz), 3.71 (3H, s), 3.25 (6H,s), 1.78 (2H, tt, J = 6.6 Hz, 5.8 Hz), 1.52 (2H, tq, J = 5.8 Hz, 7.4Hz), 0.97 (3H, t, J = 7.4 Hz). 58

¹H NMR (CDC1₃) δ 7.70 (1H, s), 7.53 (1H, d, J = 7.5 Hz), 7.33 (1H, dd, J= 7.6 Hz, 7.5 Hz), 7.29 (1H, d, J = 7.6 Hz), 5.95 (2H, brs), 5.31 (2H,s), 4.35 (2H, t, J = 6.6 Hz), 3.71 (3H, s), 3.25 (6H, s), 1.77 (2H, tt,J = 6.6 Hz, 5.8 Hz), 1.50 (2H, tq, J = 5.8 Hz, 7.4 Hz), 0.97 (3H, t, J =7.4 Hz).

TABLE 14

Ex. —R^(9a) ¹H-NMR 1 —OMe (DMSO-d₆) δ 10.02 (1H, brs), 7.93 (1H, s),7.87 (1H, d, J = 7.3 Hz), 7.59 (1H, d, J = 7.6 Hz), 7.49 (1H, t, J = 7.6Hz), 6.48 (2H, brs), 4.93 (2H, s), 4.14 (2H, t, J = 6.5 Hz), 3.84 (3H,s), 1.63 (2H, 5, J = 7.0 Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.90 (3H, t, J =7.3 Hz). 2 —OEt (DMSO-d₆) δ 10.16 (1H, brs), 7.93 (1H, s), 7.86 (1H, d,J = 7.3 Hz), 7.58 (1H, d, J = 7.8 Hz), 7.48 (1H, t, J = 7.6 Hz), 6.52(2H, brs), 4.92 (2H, s), 4.27 (2H, q, J = 7.0 Hz), 4.14 (2H, t, J = 6.5Hz), 1.63 (2H, 5, J = 7.0 Hz), 1.36 (5H, m), 0.59 (3H, t, J = 7.3 Hz). 3—OiPr (DMSO-d₆) δ 10.03 (1H, brs), 7.92 (1H, s), 7.84 (1H, d, J = 7.3Hz), 7.55 (1H, d, J = 7.8 Hz), 7.47 (1H, t, J = 7.6 Hz), 6.48 (2H, brs),5.11 (1H, 7, J = 6.5 Hz), 4.92 (2H, s), 4.14 (2H, t, J = 6.8 Hz), 1.60(2H, 5, J = 6.2 Hz), 1.34 (2H, 6, J = 7.0 Hz), 1.30 (6H, d, J = 6.2 Hz),0.89 (3H, t, J = 7.3 Hz). 4 —OCH₂CF₃ (DMSO-d₆) δ 10.03 (1H, brs), 7.96(1H, s), 7.90 (1H, d, J = 7.8 Hz), 7.65 (1H, d, J = 7.8 Hz), 7.55 (1H,t, J = 7.8 Hz), 6.49 (2H, brs), 4.97 (4H, m), 4.13 (2H, t, J = 6.5 Hz),1.61 (2H, 5, J = 7.6 Hz), 1.37 (2H, 6, J = 7.6 Hz), 0.89 (3H, t, J = 7.3Hz). 5 —O(CH₂)₂OBzl (DMSO-d₆) δ 10.32 (1H, brs), 7.94 (1H, s), 7.86 (1H,d, J = 7.6 Hz), 7.58 (1H, d, J = 7.6 Hz), 7.50 (1H, t, J = 7.6 Hz), 7.28(5H, m), 6.56 (2H, brs), 4.93 (2H, s), 4.54 (2H, s), 4.42 (2H, t, J =4.6 Hz), 4.13 (2H, t, J = 6.5 Hz), 3.74 (2H, t, J = 4.6 Hz), 1.60 (2H,5, J = 7.6 Hz), 1.34 (2H, 6, J = 7.6 Hz), 0.87 (3H, t, J = 7.6 Hz). 6—O(CH₂)₂OH (DMSO-d₆) δ 9.99 (1H, brs), 7.96 (1H, s), 7.89 (1H, d, J =7.6 Hz), 7.57 (1H, d, J = 7.6 Hz), 7.49 (1H, t, J = 7.6 Hz), 6.48 (2H,brs), 4.93 (2H, s), 4.89 (1H, m), 4.27 (2H, t, J = 5.1 Hz), 4.14 (2H, t,J = 6.8 Hz), 3.67 (2H, q, J = 5.4 Hz), 1.62 (2H, 5, J = 7.6 Hz), 1.36(2H, 6, J = 7.6 Hz), 0.89 (3H, t, J = 7.6 Hz). 7 —O(CH₂)₂NMe₂ (DMSO-d₆)δ 10.01 (1H, brs), 7.87 (1H, s), 7.85 (1H, d, J = 7.8 Hz), 7.59 (1H, d,J = 7.8 Hz), 7.50 (1H, t, J = 7.6 Hz), 6.49 (2H, brs), 4.93 (2H, s),4.33 (2H, t, J = 5.4 Hz), 4.14 (2H, t, J = 6.5 Hz), 2.58 (2H, m), 2.18(6H, s), 1.62 (2H, 5, J = 7.6 Hz), 1.36 (2H, 6, J = 7.6 Hz), 0.89 (3H,t, J = 7.6 Hz). 8

(DMSO-d₆) δ 10.10 (1H, brs), 7.89 (1H, s), 7.86 (1H, d, J = 7.8 Hz),7.60 (1H, d, J = 7.6 Hz), 7.50 (1H, t, J = 7.8 Hz), 6.51 (2H, brs), 4.93(2H, s), 4.36 (2H, t, J = 7.6 Hz), 4.14 (2H, t, J = 6.8 Hz), 3.53 (4H,t, J = 4.6 Hz), 2.65 (2H, t, J = 5.1 Hz), 2.43 (4H, t, J = 4.6 Hz), 1.62(2H, 5, J = 7.6 Hz), 1.36 (2H, 6, J = 7.6 Hz), 0.89 (3H, t, J = 7.6 Hz).9

(DMSO-d₆) δ 10.16 (1H, brs), 8.68 (1H, d, J = 1.6 Hz), 8.57 (1H, dd, J =4.6, 1.6 Hz), 7.96 (1H, s), 7.86 (2H, m), 7.50 (3H, m), 6.52 (2H, s),5.38 (2H, s), 4.93 (2H, s), 4.11 (2H, t, J = 6.5 Hz), 1.57 (2H, 5, J =6.5 Hz), 1.34 (2H, 6, J = 7.0 Hz), 0.87 (3H, t, J = 7.3 Hz). 10 —SMe(DMSO-d₆) δ 10.21 (1H, brs), 7.87 (1H, s), 7.83 (1H, d, J = 7.8 Hz),7.60 (1H, d, J = 7.6 Hz), 7.52 (1H, t, J = 7.6 Hz), 6.54 (2H, brs), 4.94(2H, s), 4.15 (2H, t, J = 6.5 Hz), 2.43 (3H, s), 1.63 (2H, 5, J = 7.0Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz).

TABLE 15

Ex. —R^(9a) ¹H-NMR 11 —OMe (DMSO-d₆) δ 10.21 (1H, brs), 7.92 (2H, d, J =8.4 Hz), 7.39 (2H, d, J = 11.1 Hz), 6.54 (2H, brs), 4.93 (2H, s), 4.11(2H, t, J = 6.8 Hz), 3.83 (3H, s), 1.62 (2H, 5, J = 6.8 Hz), 1.36 (2H,6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz). 12 —OiPr (DMSO-d₆) δ 10.02(1H, brs), 7.90 (2H, d, J = 7.8 Hz), 7.40 (2H, d, J = 8.4 Hz), 6.48 (2H,brs), 5.11 (1H, 7, J = 6.2 Hz), 4.93 (2H, s), 4.12 (2H, t, J = 6.8 Hz),1.59 (2H, 5, J = 6.2 Hz), 1.36 (8H, m), 0.88 (3H, t, J = 7.3 Hz). 13

(DMSO-d₆) δ 10.04 (1H, brs), 8.68 (1H, d, J = 1.4 Hz), 8.55 (1H, dd, J =2.1, 1.6 Hz), 7.96 (2H, d, J = 8.4 Hz), 7.88 (1H, d, J = 8.4 Hz), 7.43(3H, m), 6.49 (2H, s), 5.38 (2H, s), 4.94 (2H, s), 4.11 (2H, t, J = 6.8Hz), 1.62 (2H, 5, J = 6.8 Hz), 1.34 (2H, 6, J = 7.0 Hz), 0.87 (3H, t, J= 7.3 Hz). 14 —OBzl (DMSO-d₆) δ 10.09 (1H, brs), 7.96 (2H, d, J = 8.4Hz), 7.39 (7H, m), 6.50 (2H, s), 5.34 (2H, s), 4.94 (2H, s), 4.11 (2H,t, J = 6.8 Hz), 1.62 (2H, 5, J = 6.8 Hz), 1.34 (2H, 6, J = 7.0 Hz), 0.87(3H, t, J = 7.3 Hz).

TABLE 16

Ex. —R^(10a) ¹H-NMR 15

(DMSO-d₆) δ 10.05 (1H, brs), 7.24 (1H, d, J = 3.8 Hz), 6.51 (3H, m),4.93 (2H, s), 4.13 (2H, t, J = 6.5 Hz), 3.78 (3H, s), 1.64 (2H, 5, J =6.8 Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz). 16

(DMSO-d₆) δ 10.05 (1H, brs), 7.18 (1H, d, J = 3.5 Hz), 6.47 (3H, m),5.08 (1H, 7, J = 6.2 Hz), 4.93 (2H, s), 4.13 (2H, t, J = 6.8 Hz), 1.60(2H, 5, J = 6.2 Hz), 1.34 (2H, 6, J = 7.0 Hz), 1.18 (6H, d, J = 7.6 Hz),0.90 (3H, t, J = 7.3 Hz). 17

(DMSO-d₆) δ 10.10 (1H, brs), 8.69 (1H, d, J = 1.9 Hz), 8.02 (1H, d, J =8.4 Hz), 8.83 (1H, dd, J = 1.9, 8.4 Hz), 6.50 (2H, brs), 4.99 (2H, s),4.12 (2H, t, J = 6.8 Hz), 3.86 (3H, s), 1.62 (2H, 5, J = 6.8 Hz), 1.36(2H, 6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz). 18

(DMSO-d₆) δ 10.14 (1H, brs), 8.69 (1H, d, J = 2.2 Hz), 8.00 (1H, d, J =7.8 Hz), 7.83 (1H, dd, J = 2.2, 8.4 Hz), 6.52 (2H, brs), 5.15 (1H, 7, J= 6.2 Hz), 4.98 (2H, s), 4.12 (2H, t, J = 6.8 Hz), 1.62 (2H, 5, J = 6.8Hz), 1.36 (8H, m), 0.90 (3H, t, J = 7.3 Hz). 19

(DMSO-d₆) δ 10.01 (1H, brs), 7.19 (4H, m), 6.47 (2H, brs), 4.83 (2H, s),4.14 (2H, t, J = 6.8 Hz), 3.64 (2H, s), 3.59 (3H, s), 1.62 (2H, 5, J =6.8 Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz). 20

(DMSO-d₆) δ 10.11 (1H, brs), 7.22 (4H, m), 6.49 (2H, brs), 4.83 (2H, s),4.14 (2H, t, J = 6.5 Hz), 3.63 (2H, s), 3.58 (3H, s), 1.62 (2H, 5, J =6.8 Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz). 21

(DMSO-d₆) δ 9.98 (1H, brs), 7.20 (4H, m), 6.45 (2H, brs), 4.87 (1H, 7, J= 6.2 Hz), 4.83 (2H, s), 4.14 (2H, t, J = 6.8 Hz), 3.57 (2H, s), 1.64(2H, 5, J = 6.2 Hz), 1.34 (2H, 6, J = 7.0 Hz), 1.18 (6H, d, J = 6.5 Hz),0.87 (3H, t, J = 7.3 Hz). 22

(DMSO-d₆) δ 9.98 (1H, brs), 7.24 (2H, J = 8.4 Hz), 6.87 (2H, d, J = 8.6Hz), 6.45 (2H, brs), 4.78 (2H, s), 4.76 (2H, s), 4.15 (2H, t, J = 6.2Hz), 3.68 (3H, s), 1.63 (2H, 5, J = 6.8 Hz), 1.38 (2H, 6, J = 7.0 Hz),0.91 (3H, t, J = 7.3 Hz). 23

(DMSO-d₆) δ 9.96 (1H, brs), 7.58 (1H, d, J = 1.9 Hz), 7.24 (1H, dd, J =1.9, 8.4 Hz), 6.97 (1H, d, J = 8.4 Hz), 6.45 (2H, brs), 4.89 (2H, s),4.78 (2H, s), 4.16 (2H, t, J = 6.2 Hz), 3.68 (3H, s), 1.64 (2H, 5, J =6.8 Hz), 1.38 (2H, 6, J = 7.0 Hz), 0.91 (3H, t, J = 7.3 Hz). 24

(DMSO-d₆) δ 9.92 (1H, brs), 8.11 (1H, d, J = 1.9 Hz), 7.24 (1H, dd, J =1.9, 8.4 Hz), 6.97 (1H, d, J = 8.4 Hz), 6.45 (2H, brs), 4.89 (2H, s),4.78 (2H, s), 4.16 (2H, t, J = 6.2 Hz), 3.68 (3H, s), 1.64 (2H, 5, J =6.8 Hz), 1.38 (2H, 6, J = 7.0 Hz), 0.91 (3H, t, J = 7.3 Hz). 25

(DMSO-d₆) δ 9.99 (1H, brs), 8.11 (1H, d, J = 1.9 Hz), 7.49 (1H, dd, J =2.4, 8.4 Hz), 6.79 (1H, d, J = 8.9 Hz), 6.44 (2H, s), 4.71 (2H, s), 4.01(6H, brm), 3.04 (2H, m), 1.91 (1H, m), 1.66 (4H, m), 1.40 (3H, m), 1.16(3H, t, J = 6.8 Hz), 0.92 (3H, t, J = 7.3 Hz). 26

(DMSO-d₆) δ 9.97 (1H, brs), 7.75 (3H, m), 7.44 (1H, dd, J = 1.6 Hz, J =8.4 Hz), 7.22 (2H, m), 6.47 (2H, s), 4.98 (2H, s), 4.88 (2H, s), 4.15(4H, m), 1.62 (2H, 5, J = 6.8 Hz), 1.39 (2H, 6, J = 7.3 Hz), 1.21 (3H,t, J = 7.0 Hz), 0.88 (3H, t, J = 7.3 Hz).

TABLE 17

Ex. —R^(2a) —R^(10a) ¹H-NMR 27 —NHBu

(DMSO-d₆) δ 9.94 (1H, brs), 7.90 (2H, d, J = 8.4 Hz), 7.38 (2H, d, J =8.4 Hz), 6.20 (1H, t, J = 5.6 Hz), 6.10 (2H, brs), 4.88 (2H, s), 3.83(3H, s), 3.13 (2H, t, J = 6.8 Hz), 1.43 (2H, 5, J = 7.0 Hz), 1.25 (2H,6, J = 7.0 Hz), 0.84 (3H, t, J = 7.0 Hz). 28 —NHBu

(DMSO-d₆) δ 9.70 (1H, brs), 7.21 (1H, d, J = 3.2 Hz), 6.45 (1H, d, J =3.5 Hz), 6.26 (1H, t, J = 5.6 Hz), 6.08 (2H, brs), 4.87 (2H, s), 4.25(2H, q, J = 7.3 Hz), 3.14 (2H, t, = J 5.9 Hz), 1.43 (2H, 5, = 7.0 Hz),1.26 (5H, m), 0.86 (3H, t, J = 7.3 Hz). 29 —CH₂COOMe

(DMSO-d₆) δ 10.28 (1H, brs), 7.30 (5H, m), 6.52 (2H, s), 4.89 (2H, s),3.65 (2H, s), 3.60 (3H, s). 30 —CH₂COOEt

(DMSO-d₆) δ 10.26 (1H, brs), 7.29 (5H, m), 6.51 (2H, s), 4.89 (2H, s),4.06 (2H, q, J = 7.0 Hz), 3.63 (2H, s), 1.15 (3H, t, J = 7.0 Hz).(DMSO-d₆) δ 9.76 (1H, s), 7.29 (5H, m), 6.64 (1H, t, J = 6.2 Hz), 6.12(2H, brs), 4.78 (2H, s), 3.90 (1H, d, J = 4.3 Hz), 3.57 (3H, s). 31—NHCH₂COOMe

(DMSO-d₆) δ 9.76 (1H, s), 7.29 (5H, m), 6.64 (1H, t, J = 6.2 Hz), 6.12(2H, brs), 4.78 (2H, s), 3.90 (1H, d, J = 4.3 Hz), 3.57 (3H, s). 32—NHCH₂COOMe

(DMSO-d₆) δ 9.70 (1H, brs), 8.40 (1H, d, J = 2.0 Hz), 7.53 (1H, dd, J =8.0, 2.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 6.65 (1H, t, J = 7.1 Hz), 6.11(2H, brs), 4.79 (2H, s), 3.92 (2H, d, J = 7.1 Hz), 3.60 (3H, s), 2.42(3H, s). 33 —NH(CH₂)₂OCOMe

(DMSO-d₆) δ 9.68 (1H, s), 8.42 (1H, d, J = 2.0 Hz), 7.59 (1H, dd, J =8.0, 2.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 6.38 (1H, t, J = 5.2 Hz), 6.08(2H, brs), 4.79 (2H, s), 4.07 (2H, t, J = 5.2 Hz), 3.40 (2H, q, J = 5.2Hz), 2.41 (3H, s), 1.99 (3H, s). 34 —NH(CH₂)₂OCOOMe

(DMSO-d₆) δ 9.68 (1H, s), 8.42 (1H, d, J = 2.0 Hz), 7.58 (1H, dd, J =8.0, 2.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 6.42 (1H, t, J = 5.6 Hz), 6.08(2H, brs), 4.79 (2H, s), 4.15 (2H, t, J = 5.6 Hz), 3.68 (3H, s), 3.40(2H, q, J = 5.6 Hz), 2.42 (3H, s). 35 —NH(CH₂)₂OCOMe

(DMSO-d₆) δ 9.73 (1H, s), 7.26 (5H, m), 6.36 (1H, t, J = 6.0 Hz), 6.09(2H, brs), 4.80 (2H, s), 4.07 (2H, t, J = 6.0 Hz), 3.40 (2H, q, J = 6.0Hz), 1.98 (3H, s). 36 —O(CH₂)₂OCOMe

(DMSO-d₆) δ 9.95 (1H, brs), 8.43 (1H, d, J = 1.6 Hz), 7.59 (1H, dd, J =8.0, 1.6 Hz), 7.20 (1H, d, J = 8.0 Hz), 6.51 (1H, brs), 4.85 (2H, s),4.35 (2H, m), 4.29 (2H, m), 2.42 (3H, s), 2.03 (3H, s). 37 —O(CH₂)₂OCOEt

(DMSO-d₆) δ 9.86 (1H, brs), 8.43 (1H, d, J = 2.0 Hz), 7.58 (1H, dd, J =8.0, 2.0 Hz), 7.21 (1H, d, J = 8.0 Hz), 6.51 (1H, brs), 4.84 (2H, s),4.35 (2H, m), 4.29 (2H, m), 2.42 (3H, s), 2.33 (2H, q, J = 7.6 Hz), 1.01(3H, t, J = 7.6 Hz). 38 —O(CH₂)₂OCOOMe

(DMSO-d₆) δ 10.00 (1H, s), 8.43 (1H, d, J = 2.0 Hz), 7.60 (1H, dd, J =8.0, 2.0 Hz), 7.21 (1H, d, J = 8.0 Hz), 6.52 (1H, brs), 4.85 (2H, s),4.36 (4H, s), 3.70 (3H, s), 2.42 (3H, s). 39 —O(CH₂)₂OCONMe₂

(DMSO-d₆) δ 8.42 (1H, d, J = 1.6 Hz), 7.56 (1H, dd, J = 8.0, 1.6 Hz),7.58 (1H, d, J = 8.0 Hz), 7.11 (1H, brs), 6.56 (2H, brs), 4.84 (2H, s),4.34 (2H, m), 4.24 (2H, m), 2.82 (6H, s), 2.42 (3H, s).

TABLE 18

Ex. R^(2a) ¹H-NMR 40 —SCH₂COOMe (DMSO-d₆) δ 810.12 (1H, brs), 7.30 (5H,m), 6.57 (2H, brs), 4.84 (2H, s), 3.91 (3H, s), 3.56 (2H, s). 41—SCH₂COOEt (DMSO-d₆) δ 10.12 (1H, brs), 7.31 (5H, m), 6.57 (2H, brs),4.85 (2H, s), 4.01 (2H, q, J = 7.1 Hz), 3.90 (2H, s), 1.12 (3H, t, J =7.1 Hz). 42 —SCH₂COO(CH₂)₇CH₃ (DMSO-d₆) δ 10.12 (1H, brs), 7.28 (5H, m),6.56 (2H, brs), 4.84 (2H, s), 3.96 (2H, t, J = 6.5 Hz), 3.90 (2H, s),1.45 (2H, m), 1.24 (2H, m), 1.11 (8H, m), 0.83 (3H, t, J = 7.3 Hz). 43—SCH₂COOtBu (DMSO-d₆) δ 10.13 (1H, brs), 7.29 (5H, m), 6.55 (2H, brs),4.87 (2H, s), 3.82 (2H, s), 1.37 (9H, s). 44 —SCH₂COOCH₂CH═CH₂ (DMSO-d₆)δ 10.13 (1H, brs), 7.28 (5H, m), 6.58 (2H, brs), 5.86 (1H, m), 5.70 (2H,m), 4.84 (2H, s), 4.51 (2H, m), 3.96 (2H, s). 45 —SCH₂COOBz1 (DMSO-d₆) δ10.11 (1H, brs), 7.28 (10H, m), 6.57 (2H, brs), 5.06 (2H, s), 4.72 (2H,s), 3.97 (2H, s). 46 —SCH₂COO(CH₂)₂F (DMSO-d₆) δ 10.13 (1H, brs), 7.29(5H, m), 6.56 (2H, brs), 4.84 (2H, s), 4.54 (2H, dt, J = 47.7 Hz, 7.0Hz), 4.23 (2H, dt, J = 30.2 Hz, 7.0 Hz), 3.96 (2H, s). 47 —CH₂COOCH₂CF₂H(DMSO-d₆) δ 10.14 (1H, brs), 7.28 (5H, m), 6.57 (2H, brs), 6.20 (1H, m),4.84 (2H, s), 4.27 (2H, m), 4.00 (2H, s). 48 —SCH₂COOCH₂CF₃ (DMSO-d₆) δ10.14 (1H, brs), 7.28 (5H, m), 6.58 (2H, brs), 4.81 (2H, s), 4.63 (2H,m), 4.04 (2H, s). 49 —SCH₂COO(CH₂)₂OMe (DMSO-d₆) δ 10.13 (1H, brs), 7.28(5H, m), 6.56 (2H, brs), 4.85 (2H, s), 4.10 (2H, t, J = 4.7 Hz), 3.92(2H, s), 3.46 (2H, t, J = 4.7 Hz), 3.19 (3H, s). 50 —SCH₂CONHEt(DMSO-d₆) δ 10.13 (1H, brs), 7.95 (1H, brs), 7.28 (5H, m), 6.58 (2H, s),4.88 (2H, s), 3.71 (2H, s), 3.02 (2H, m), 0.94 (3H, t, J = 7.2 Hz). 51

(DMSO-d₆) δ 10.13 (1H, brs), 7.30 (5H, 6.57 (2H, brs), 4.88 (2H, s),4.21 (2H, s), 3.43 (2H, m), 3.38 (2H, m), 1.54 (2H, m), 1.46 (2H, m),1.38 (2H, m). 52

(DMSO-d₆) δ 10.13 (1H, brs), 7.30 (5H, m), 6.57 (2H, brs), 4.88 (2H, s),4.05 (2H, s), 3.44 (8H, m). 53

(DMSO-d₆) δ 10.13 (1H, brs), 7.29 (5H, m), 6.59 (2H, brs), 4.89 (1H, d,J = 15.3 Hz), 4.82 (1H, d, J = 15.3 Hz), 4.36 (1H, d, J = 7.3 Hz), 4.03(2H, q, J 7.1 Hz), 1.47 (3H, d, J = 7.3 Hz), 1.11 (3H, t, J = 7.1 Hz).54 —S(CH₂)₂COOMe (DMSO-d₆) δ 10.12 (1H, s), 7.30 (5H, m), 6.55 (2H,brs), 4.87 (2H, s), 3.60 (3H, s), 3.19 (2H, t, J = 7.2 Hz), 2.74 (2H, t,J = 7.2 Hz). 55 —S(CH₂)₂COOEt (DMSO-d₆) δ 10.12 (1H, brs), 7.27 (5H, m),6.55 (2H, brs), 4.87 (2H, s), 4.07 (2H, q, J = 7.1 Hz), 3.20 (2H, t, 7.0Hz), 2.70 (2H, t, J = 7.0 Hz), 1.17 (3H, t, J = 7.1 Hz). 56—S(CH₂)₃COOEt (DMSO-d₆) δ 10.11 (1H, brs), 7.30 (5H, m), 6.53 (2H, brs),4.89 (2H, s), 4.04 (2H, q, J = 7.1 Hz), 3.04 (2H, t, J = 7.3 Hz), 2.38(2H, t, J = 7.4 Hz), 1.88 (2H, m), 1.16 (3H, t, J = 7.1 Hz). 57—S(CH₂)₄COOEt (DMSO-d₆) δ 10.11 (1H, brs), 7.28 (5H, m), 6.52 (2H, brs),4.89 (2H, s), 4.03 (2H, q, J = 7.1 Hz), 3.00 (2H, t, J = 6.6 Hz), 2.28(2H, t, J = 7.0 Hz), 1.61 (4H, m), 1.16 (3H, t, J = 7.1 Hz). 58—SCH₂COCH₂COOEt (DMSO-d₆) δ 10.14 (1H, brs), 7.30 (5H, m), 6.58 (2H,brs), 4.87 (2H, s), 4.10 (2H, q, J = 7.1 Hz), 3.92 (2H, s), 3.71 (2H,s), 1.15 (3H, t, J = 7.1 Hz). 59

(DMSO-d₆) δ 10.17 (1H, brs), 7.29 (5H, m), 6.61 (2H, brs), 4.90 (1H, d,J = 15.4 Hz), 4.84 (1H, d, J = 15.4 Hz), 4.40 (1H, t, J = 9.9 Hz), 4.22(2H, m), 2.61 (1H, m), 2.41 (1H, m).

TABLE 19

Ex. R^(2a) R^(10a) ¹H-NMR 60

(DMSO-d₆) δ 9.73 (1H, brs), 8.42 (1H, d, J = 2.0 Hz), 7.57 (1H, dd, J =8.0, 2.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 6.60 (1H, t, J = 6.0 Hz), 6.14(2H, brs), 4.89 (1H, m), 4.80 (2H, s), 4.50 (1H, t, J = 8.0 Hz), 4.33(1H, dd, J = 8.4, 6.0 Hz), 3.56 (1H, m), 3.45 (1H, m), 2.42 (3H, s). 61—(CH₂)₂COOMe

(DMSO-d₆) δ 10.21 (1H, brs), 7.28 (5H, m), 6.40 (2H, s), 4.87 (2H, s),3.53 (3H, s), 2.87 (2H, d, J = 6.9 Hz), 2.71 (2H, d, J = 6.9 Hz). 62—(CH₂)₂COOEt

(DMSO-d₆) δ 10.14 (1H, brs), 7.28 (5H, m), 6.39 (2H, s), 4.87 (2H, s),3.98 (2H, q, J = 7.1 Hz), 2.88 (2H, d, J = 7.0 Hz), 2.69 (2H, d, J = 7.0Hz), 1.11 (3H, d, J = 7.1 Hz). 63 —(CH₂)₂COSMe

(DMSO-d₆) δ 10.18 (1H, brs), 7.27 (5H, m), 6.42 (2H, s), 4.88 (2H, s),2.87 (2H, d, J = 6.6 Hz), 2.71 (2H, d, J = 6.6 Hz), 2.20 (3H, s). 64—OCH₂COOMe

(DMSO-d₆) δ 10.06 (1H, brs), 7.28 (5H, m), 6.57 (2H, brs), 4.82 (2H, s),4.78 (2H, s), 3.61 (3H, s). 65 —OCH₂COOEt

(DMSO-d₆) δ 10.02 (1H, brs), 7.29 (5H, m), 6.54 (2H, brs), 4.83 (2H, s),4.75 (2H, s), 4.07 (2H, q, J = 7.1 Hz), 1.14 (3H, d, J = 7.1 Hz). 66—(CH₂)₂COOMe

(DMSO-d₆) δ 10.14 (1H, brs), 8.43 (1H, d, J = 2.0 Hz), 7.59 (1H, dd, J =8.0, 2.3 Hz), 7.19 (1H, d, J = 8.0 Hz), 6.40 (2H, brs), 4.85 (2H, s),3.56 (3H, s), 2.88 (2H, d, J = 6.9 Hz), 2.72 (2H, d, J = 6.9 Hz), 2.41(3H, s). 67 —(CH₂)₂COOMe

(DMSO-d₆) δ 10.16 (1H, brs), 7.24 (2H, d, J = 8.2 Hz), 7.19 (2H, d, J =8.2 Hz), 6.39 (2H, brs), 4.85 (2H, s), 3.64 (2H, s), 3.58 (3H, s), 3.53(3H, s), 2.87 (2H, d, J = 6.9 Hz), 2.71 (2H, d, J = 6.9 Hz).

TABLE 20

Ex. R^(10a) ¹H-NMR 68

(DMSO-d₆) δ 9.95 (1H, brs), 7.23 (2H, d, J = 8.3 Hz), 7.20 (2H, d, J =8.3 Hz), 6.46 (2H, brs), 4.83 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 4.04(2H, q, J = 7.1 Hz), 3.61 (2H, s), 1.62 (2H, 5, J = 6.6 Hz), 1.36 (2H,6, J = 6.6 Hz), 1.16 (3H, t, J = 7.1 Hz), 0.90 (3H, t, J = 7.3 Hz). 69

(DMSO-d₆) δ 10.01 (1H, brs), 7.25 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J =8.5 Hz), 6.47 (2H, brs), 4.83 (2H, s), 4.13 (2H, q, J = 9.1 Hz), 4.13(2H, t, J = 6.6 Hz), 3.79 (2H, s), 1.62 (2H, 5, J = 7.0 Hz), 1.37 (2H,6, J = 7.5 Hz), 0.90 (3H, t, J = 7.4 Hz). 70

(DMSO-d₆) δ 10.00 (1H, brs), 7.24 (2H, d, J = 8.6Hz), 7.21 (2H, d, J =8.8 Hz), 6.46 (2H, brs), 4.83 (2H, s), 4.66 (1H, t, J = 4.0 Hz), 4.54(1H, t, J = 4.0 Hz), 4.30 (1H, t, J = 4.0Hz), 4.23 (1H, t, J = 4.0 Hz),4.13 (2H, t, J = 6.6 Hz), 3.68 (2H, s), 1.62 (2H, 5, J = 6.7 Hz), 1.36(2H, 6, J = 7.6 Hz), 0.90 (3H, t, J = 7.3 Hz). 71

(DMSO-d₆) δ 9.98 (1H, brs), 7.24 (2H, d, J = 8.5Hz), 7.21 (2H, d, J =8.5 Hz), 6.46 (2H, brs), 4.83 (2H, s), 4.81 (1H, t, J = 5.5 Hz), 4.13(2H, t, J = 6.6 Hz), 4.02 (2H, t, J = 5.2 Hz), 3.64 (2H, s), 3.55 (2H,q, J = 5.4 Hz), 1.62 (2H, 5, J = 6.7 Hz), 1.36 (2H, 6, J = 7.5 Hz), 0.90(3H, t, J = 7.4 Hz). 72

(DMSO-d₆) δ 10.13 (1H, brs), 9.78 (1H, brs), 7.25 (4H, m), 6.56 (2H,brs), 4.84 (2H, s), 4.33 (2H, t, J = 5.0 Hz), 4.14 (2H, t, J = 6.6Hz),3.70 (2H, s), 3.35 (2H, q, J = 5.0 Hz), 2.76 (3H, s), 2.75 (3H, s), 1.62(2H, 5, J = 7.9 Hz), 1.37 (2H, 6, J = 7.6 Hz), 0.90 (3H, t, J = 7.4 Hz).73

(DMSO-d₆) δ 9.97 (1H, brs), 7.23 (4H, m), 6.45 (2H, brs), 4.83 (2H, s),4.12 (4H, m), 3.62 (2H, s), 3.48 (4H, t, J = 4.7 Hz), 2.48 (2H, t, J =5.7 Hz), 2.32 (4H, t, J = 4.8 Hz), 1.62 (2H, 5, J = 7.8 Hz), 1.36 (2H,6, J = 7.3 Hz), 0.90 (3H, t, J = 7.3 Hz). 74

(DMSO-d₆) δ 10.00 (1H, brs), 7.23 (4H, m), 6.46 (2H, brs), 4.83 (2H, s),4.13 (2H, t, J = 6.6 Hz), 3.87 (2H, s), 2.20 (2H, s), 1.62 (2H, 5, J =7.8 Hz), 1.37 (2H, 6, J = 7.4 Hz), 0.90 (3H, t, J = 7.4 Hz). 75

(DMSO-d₆) δ 9.99 (1H, brs), 7.24 (2H, d, J = 8.4 Hz), 7.21 (2H, d, J =8.4 Hz), 6.46 (2H, brs), 4.83 (2H, s), 4.13 (2H, t, J = 6.6 Hz), 3.85(2H, s), 2.78 (2H, q, J = 7.4 Hz), 1.62 (2H, 5, J = 6.7 Hz), 1.36 (2H,6, J = 7.3 Hz), 1.12 (3H, t, J = 7.4 Hz), 0.90 (3H, t, J = 7.4 Hz). 76

(DMSO-d₆) δ 9.93 (1H, brs), 7.43 (1H, s), 7.21 (2H, d, J = 8.4Hz), 7.18(2H, d, J = 8.3 Hz), 6.85 (1H, s), 6.44 (2H, brs), 4.81 (2H, s), 4.14(2H, t, J = 6.7 Hz), 3.32 (2H, s), 1.62 (2H, 5, J = 6.6 Hz), 1.37 (2H,6, J = 7. 5 Hz), 0.90 (3H, t, J = 7.3 Hz). 77

(DMSO-d₆) δ 9.96 (1H, brs), 7.91 (1H, d, J = 4.3 Hz), 7.21 (2H, d, J =8.3 Hz), 7.18 (2H, d, J = 8.3 Hz), 6.45 (2H, brs), 4.81 (2H, s), 4.14(2H, t, J = 6.6 Hz), 2.54 (2H, s), 2.53 (3H, s), 1.62 (2H, 5, J = 6.7Hz), 1.37 (2H, 6, J = 7.6 Hz), 0.90 (3H, t, J = 7.3 Hz). 78

(DMSO-d₆) δ 9.99 (1H, brs), 7.21 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J =8.1 Hz), 6.46 (2H, brs), 4.82 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 3.63(2H, s), 2.97 (3H, s), 2.80 (3H, s), 1.62 (2H, 5, J = 6.6 Hz), 1.37 (2H,6, J = 7.6 Hz), 0.90 (3H, t, J = 7.3 Hz). 79

(DMSO-d₆) δ 9.95 (1H, brs), 7.22 (2H, d, J = 8.0 Hz), 7.15 (2H, d, J =8.0 Hz), 6.45 (2H, brs), 4.82 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 3.67(2H, s), 3.46 (8H, m), 1.62 (2H, 5, J = 7.7 Hz), 1.37 (2H, 6, J = 7.4Hz), 0.90 (3H, t, J = 7.3 Hz). 80

(DMSO-d₆) δ 9.98 (1H, brs), 7.27 (1H, t, J = 8.0 Hz), 7.16 (3H, m), 6.46(2H, brs), 4.83 (2H, s), 4.13 (2H, t, J = 6.6 Hz), 4.03 (2H, q, J = 7.1Hz), 3.58 (2H, s), 1.62 (2H, 5, J = 6.6 Hz), 1.36 (2H, 6, J = 7.5 Hz),1.14 (3H, t, J = 7.1 Hz), 0.90 (3H, t, J = 7.3 Hz). 81

(DMSO-d₆) δ 9.99 (1H, brs), 6.46 (2H, brs), 6.19 (2H, m), 4.79 (2H, s),4.14 (2H, t, J = 6.6 Hz), 3.72 (2H, s), 3.60 (3H, s), 1.62 (2H, 5, J =6.8 Hz), 1.36 (2H, 6, J = 7.4 Hz), 0.90 (3H, t, J = 7.3 Hz). 82

(DMSO-d₆) δ 10.08 (1H, brs), 8.69 (1H, d, J = 0.9 Hz), 7.89 (2H, m),6.51 (2H, brs), 5.00 (2H, s), 4.12 (2H, t, J = 6.6 Hz), 2.35 (3H, s),1.62 (2H, 5, J = 6.8 Hz), 1.36 (2H, 6, J = 7.3 Hz), 0.88 (3H, t, J = 7.4Hz). 83

(DMSO-d₆) δ 10.01 (1H, brs), 8.61 (1H, d, J = 1.7 Hz), 8.09 (1H, brs),7.98 (1H, d, J = 8.0 Hz), 7.83 (1H, dd, J = 2.1, 8.0 Hz), 7.63 (1H,brs), 6.49 (2H, brs), 4.98 (2H, s), 4.13 (2H, t, J = 6.6 Hz), 1.61 (2H,5, J = 6.6 Hz), 1.35 (2H, 6, J = 7.5 Hz), 0.89 (3H, t, J = 7.4 Hz). 84

(DMSO-d₆) δ 9.99 (1H, brs), 7.15 (4H, m), 6.46 (2H, brs), 4.81 (2H, s),4.14 (2H, t, J = 6.6 Hz), 3.54 (3H, s), 2.80 (2H, t, J = 7.6Hz), 2.58(2H, t, J = 7.6 Hz), 1.62 (2H, 5, J = 6.6 Hz), 1.36 (2H, 6, J = 7.6 Hz),0.90 (3H, t, J = 7.3 Hz). 85

(DMSO-d₆) δ 9.93 (1H, brs), 7.21 (2H, d, J = 8.3 Hz), 7.15 (2H, d, J =8.3 Hz), 6.44 (2H, brs), 4.80 (2H, s), 4.13 (2H, t, J = 6.6 Hz), 3.56(3H, s), 2.80 (2H, t, J = 7.7 Hz), 2.59 (2H, t, J = 7.5 Hz), 1.62 (2H,5, J = 6.6 Hz), 1.36 (2H, 6, J = 7.3 Hz), 0.90 (3H, t, J = 7.3 Hz). 86

(DMSO-d₆) δ 9.97 (1H, brs), 7.20 (2H, d, J = 8.3 Hz), 7.15 (2H, d, J =8.3 Hz), 6.45 (2H, brs), 4.80 (2H, s), 4.13 (2H, t, J = 6.6Hz), 4.01(2H, q, J = 7.1 Hz), 2.79 (2H, t, J = 7.4 Hz), 2.56 (2H, t, J = 7.7 Hz),1.62 (2H, 5, J = 7.0 Hz), 1.36 (2H, 6, J = 7.6 Hz), 1.12 (3H, t, J = 7.1Hz), 0.90 (3H, t, J = 7.3 Hz). 87

(DMSO-d₆) δ 9.90 (1H, brs), 8.10 (1H, d, J = 2.1 Hz), 7.49 (1H, dd, J =2.3, 8.9 Hz), 6.79 (1H, d, J = 8.8 Hz), 6.42 (2H, brs), 4.71 (2H, s),4.15 (4H, m), 3.59 (3H, s), 2.86 (2H, t, J = 11.0 Hz), 2.58 (2H, m),1.84 (1H, m), 1.63 (2H, 5, J = 7.8 Hz), 1.48 (2H, m), 1.38 (2H, 6, J =7.3 Hz), 0.92 (3H, t, J = 7.3 Hz). 88

(DMSO-d₆) δ 9.93 (1H, brs), 8.11 (1H, d, J = 2.3 Hz), 7.49 (1H, dd, J =2.4, 8.8 Hz), 6.79 (1H, d, J = 8.8 Hz), 6.43 (2H, s), 4.71 (2H, s), 4.31(1H, m), 4.16 (2H, t, J = 6.6 Hz), 3.94 (1H, m), 2.99 (2H, m), 2.45 (1H,m), 1.93 (1H, m), 1.62 (4H, m), 1.39 (3H, m), 0.92 (3H, t, J = 7.3 Hz).89

(DMSO-d₆) δ 9.97 (1H, brs), 7.81 (1H, d, J = 9.0 Hz), 7.75 (1H, d, J =8.6 Hz), 7.71 (1H, s), 7.43 (1H, d, J = 7.2 Hz), 7.26 (1H, d, J =2.2Hz), 7.19 (1H, dd, J = 2.5, 9.0 Hz), 6.46 (2H, s), 4.98 (2H, s), 4.90(2H, s), 4.14 (2H, t, J = 6.6 Hz), 3.71 (3H, s), 1.61 (2H, 5, J = 7.1Hz), 1.35 (2H, 6, J = 7.6 Hz), 0.88 (3H, t, J = 7.4 Hz). 90

(DMSO-d₆) δ 10.03 (1H, brs), 7.72 (1H, d, J = 8.0 Hz), 7.64 (1H, d, J =1.5 Hz), 7.59 (1H, dd, J = 1,7, 8.0 Hz), 6.49 (2H, brs), 4.95 (2H, s),4.12 (2H, t, J = 6.6 Hz), 3.80 (6H, s), 1.60 (2H, 5, J = 6.6 Hz), 1.35(2H, 6, J = 7.5 Hz), 0.89 (3H, t, J = 7.4 Hz). 91

(DMSO-d₆) δ 10.10 (1H, brs), 8.38 (1H, m), 8.18 (2H, d, J = 1.6 Hz),6.52 (2H, brs), 5.00 (2H, s), 4.15 (2H, t, J = 6.6 Hz), 3.88 (6H, s),1.62 (2H, 5, J = 6.6 Hz), 1.36 (2H, 6, J = 7.5 Hz), 0.89 (3H, t, J = 7.4Hz). 92

(DMSO-d₆) δ 9.98 (1H, brs), 8.47 (1H, d, J = 1.8 Hz), 7.66 (1H, dd, J =2.3, 8.0 Hz), 7.31 (1H, d, J = 7.9 Hz), 6.46 (2H, brs), 4.87 (2H, s),4.14 (2H, t, J = 6.6 Hz), 3.59 (2H, s), 3.43 (3H, s), 1.62 (2H, 5, J =7.0 Hz), 1.36 (2H, 6, J = 7.6 Hz), 0.90 (3H, t, J = 7.3 Hz). 93

(DMSO-d₆) δ 9.99 (1H, brs), 8.38 (1H, d, J = 1.6 Hz), 7.60 (1H, dd, J =2.2, 8.3 Hz), 7.34 (1H, d, J = 8.3 Hz), 6.47 (2H, brs), 4.84 (2H, s),4.64 (1H, t, J = 9.6 Hz), 4.39 (1H, dt, J = 3.2, 8.7 Hz), 4.31 (1H, q, J= 8.7 Hz), 4.14 (2H, t, J = 6.6 Hz), 2.69 (1H, m), 2.33 (1H, m), 1.62(2H, 5, J = 7.0 Hz), 1.37 (2H, 6, J = 7.5 Hz), 0.91 (3H, t, J = 7.3 Hz).94

(DMSO-d₆) δ 9.96 (1H, brs), 7.26 (2H, d, J = 8.3 Hz), 6.98 (2H, d, J =8.3 Hz), 6.45 (2H, brs), 5.29 (1H, t, J = 8.7 Hz), 4.79 (2H, s), 4.39(1H, dt, J = 2.3, 8.8 Hz), 4.31 (1H, m), 4.15 (2H, t, J = 6.6 Hz), 2.74(1H, m), 2.22 (1H, m), 1.63 (2H, 5, J = 6.6 Hz), 1.37 (2H, 6, J = 7.6Hz), 0.91 (3H, t, J = 7.3 Hz). 95

(DMSO-d₆) δ 9.96 (1H, brs), 7.22 (2H, d, J = 8.7 Hz), 6.81 (2H, d, J =8.7 Hz), 6.44 (2H, brs), 4.86 (1H, m), 4.76 (2H, s), 4.67 (1H, t, J =5.1 Hz), 4.14 (2H, t, J = 6. 7Hz), 3.65 (3H, s), 3.53 (2H, m), 1.94 (2H,m), 1.63 (2H, 5, J = 6.6 Hz), 1.37 (2H, 6, J = 7.4 Hz), 0.91 (3H, t, J =7.3 Hz).

TABLE 21 Ex. Structure ¹H-NMR 96

(DMSO-d₆) δ 9.96 (1H, s), 7.27 (1H, dd, J = 7.6 Hz, 7.6 Hz), 7.20 (1H,s), 7.17 (1H, d, J = 7.6 Hz), 7.15 (1H, d, J = Hz), 3.65 (2H, s), 3.58(3H, s), 7.6 Hz), 6.47 (2H, brs), 4.83 (2H, s), 4.25 (2H, t, J = 4.83.58 (2H, t, J = 4.8 Hz), 3.26 (3H, s). 97

(DMSO-d₆) δ 9.63 (1H, s), 7.26 (1H, dd, J = 7.6 Hz, 7.6 Hz), 7.19 (1H,s), 7.16-7.13 (2H, m), 6.20 (1H, t, J = 5.6 Hz), 6.00 (2H, s), 4.83 (2H,s), 3.77 (2H, s), 3.59 (3H, s), 3.15 (2H, dt, J = 5.6 Hz, 6.8 Hz), 1.43(2H, tt, J = 7.6 Hz, 6.8 Hz), 1.28 (2H, tq, J = 7.6 Hz, 7.6 Hz), 0.86(3H, t, J = 7.6 Hz). 98

(DMSO-d₆) δ 10.37 (1H, brs), 7.29 (1H, dd, J = 8.0 Hz, 4.8 Hz),7.18-7.12 (3H, m), 6.91 (2H, brs), 4.88 (2H, s), 3.65 (2H, s), 3.58 (3H,s). 99

(DMSO-d₆) δ 10.12 (1H, s), 7.28 (1H, dd, J = 7.6 Hz, 7.6 Hz), 7.23 (1H,s), 7.21 (1H, d, J = 7.6 Hz), 7.16 (1H, d, J = 7.6 Hz), 6.53 (2H, brs),4.88 (1H, brs), 4.85 (2H, s), 3.65 (2H, s), 3.61-3.57 (2H, m), 3.59 (3H,s), 3.12 (2H, t, J = 6.8 Hz). 100

(DMSO-d₆) δ 9.93 (1H, brs), 7.28 (1H, dd, J = 7.6 Hz, 7.6 Hz), 7.23 (1H,s), 7.21 (1H, d, J = 7.6 Hz), 7.16 (1H, d, J = 7.6 Hz), 6.53 (2H, brs),4.88 (1H, brs), 4.85 (2H, s), 3.65 (2H, s), 3.61-3.57 (2H, m), 3.59 (3H,s), 3.12 (2H, t, J = 6.8 Hz). 101

(DMSO-d₆) δ 9.93 (1H, brs), 7.30-7.11 (4H, m), 6.43 (2H, brs), 4.83 (2H,s), 4.14 (2H, t, J = 6.6 Hz), 3.52 (2H, s), 3.58 (3H, s), 1.62 (2H, 5, J= 6.9 Hz), 1.45 (6H, s), 1.36 (2H, 6, J = 7.0 Hz), 0.89 (3H, t, J = 7.2Hz). 102

(DMSO-d₆) δ 9.81 (1H, brs), 7.82 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J =8.2 Hz), 6.37 (2H, brs), 4.09 (2H, t, J = 6.6 Hz), 3.93 (2H, t, J = 7.0Hz), 3.81 (3H, s), 3.06 (2H, t, J = 7.1 Hz), 1.61 (2H, 5, J = 7.0 Hz),1.37 (2H, 6, J = 7.4 Hz), 0.90 (3H, t, J = 7.3 Hz).

TABLE 22

Ex. —R^(2a) ¹H-NMR 103

(DMSO-d₆) δ 810.14 (1H, brs), 8.05 (1H, s), 7.79 (1H, d, J = 7.8 Hz),7.64 (1H, d, J = 7.8 Hz), 7.34 (1H, t, J = 7.8 Hz), 7.28 (5H, m), 6.60(2H, brs), 4.92 (2H, s), 4.36 (2H, s), 3.82 (3H, s). 104

(DMSO-d₆) δ 10.15 (1H, brs), 7.77 (2H, d, J = 8.2 Hz), 7.49 (2H, d, J =8.2 Hz) 7.28 (5H, m), 6.61 (2H, brs), 4.92 (2H, s), 4.35 (2H, s), 3.83(3H, s). 105

(DMSO-d₆) δ 10.13 (1H, brs), 7.29 (7H, m), 7.18 (1H, t, J = 7.6 Hz),7.09 (2H, d, J = 7.6 Hz), 6.59 (2H, brs), 4.91 (2H, s), 4.27 (2H, s),3.60 (2H, s), 3.58 (3H, s). 106

(DMSO-d₆) δ 10.13 (1H, brs), 7.27 (7H, m), 7.09 (2H, d, J = 8.0 Hz),6.58 (2H, brs), 4.91 (2H, s), 4.27 (2H, s), 3.61 (2H, s), 3.59 (3H, s).107

(DMSO-d₆) δ 10.11 (1H, s), 7.18 (5H, m), 6.40 (2H, s), 4.80 (2H, s),3.93 (2H, t, J = 6.6 Hz), 3.55 (2H, s), 1.42 (2H, m), 1.17 (2H, m), 0.74(3H, t, J = 7.4 Hz). 108

(DMSO-d₆) δ 10.26 (1H, brs), 7.32 (5H, m), 6.53 (2H, s), 4.94 (3H, m),3.64 (2H, s), 1.19 (6H, t, J = 6.3 Hz). 109

(DMSO-d₆) δ 10.03 (1H, brs), 7.09 (5H, m), 6.32 (2H, s), 4.70 (2H, s),4.39 (2H, m), 4.08 (2H, m), 3.50 (2H, s). 110

(DMSO-d₆) δ 10.13 (1H, s), 7.24 (5H, m), 6.40 (2H, brs), 4.83 (2H, s),3.63 (2H, s), 3.44-3.32 (8H, m).

TABLE 23

Ex. —R^(10a) ¹H-NMR 111

(DMSO-d₆) δ 89.97 (1H, brs), 7.21 (4H, s), 6.43 (2H, brs), 4.85 (2H, s),4.12 (2H, t, J = 6.6 Hz), 4.01 (2H, s), 3.58 (3H, s), 1.61 (2H, 5, J =6.6 Hz), 1.36 (2H, 6, J = 7.3 Hz), 0.89 (3H, t, J = 7.3 Hz). 112

(DMSO-d₆) δ 9.98 (1H, brs), 7.87-7.84 (1H, m), 7.60-7.58 (1H, m),7.34-7.27 (1H, m), 6.45 (2H, brs), 4.88 (2H, s), 4.13 (2H, t, J = 6.6Hz), 3.82 (3H, s), 1.61 (2H, 5, J = 6.8 Hz), 1.35 (2H, 6, J = 7.5 Hz),0.88 (3H, t, J = 7.3 Hz). 113

(DMSO-d₆) δ 9.93 (1H, brs), 7.63 (1H, d, 2.4 Hz), 7.48 (1H, dd, J = 2.4Hz, 8.6 Hz), 7.10 (1H, d, J = 8.8 Hz), 6.43 (2H, brs), 4.80 (2H, s),4.14 (2H, t, J = 6.6 Hz), 3.77 (3H, s), 3,75 (3H, s), 1.62 (2H, 5, J =6.8 Hz), 1.36 (2H, 6, J = 7.5 Hz), 0.89 (3H, t, J = 7.3 Hz). 114

(DMSO-d₆) δ 9.96 (1H, brs), 7.24 (4H, s), 6.44 (2H, brs), 4.81 (2H, s),4.13 (2H, t, J = 6.6 Hz), 3.55 (3H, s), 1.61 (2H, 5, J = 6.8 Hz), 1.45(6H, s), 1.36 (2H, 6, J = 7.5 Hz), 0.90 (3H, t, J = 7.3 Hz). 115

(DMSO-d₆) δ 9.96 (1H, brs), 7.29-7.12 (4H, m), 6.44 (2H, brs), 4.82 (2H,s), 4.13 (2H, t, J = 6.6 Hz), 3.75 (1H, q, J = 7.1 Hz), 3.54 (3H, s),1.61 (2H, 5, J = 6.8 Hz), 1.36 (2H, 6, J = 7.5 Hz), 1.33 (3H, d, J =7.1), 0.89 (3H, t, J = 7.3 Hz). 116

(DMSO-d₆) δ 10.05 (1H, brs), 7.91 (1H, s), 7.88 (1H, d, J = 7.7 Hz),7.69 (1H, d, J = 7.6 Hz), 7.58 (1H, dd, J = 7.7 Hz, 7.6 Hz), 6.50 (2H,brs), 4.96 (2H, s), 4.13 (2H, t, J = 6.6 Hz), 3.91 (3H, s), 1.61 (2H,tt, J = 7.4 Hz, 6.6 Hz), 1.37 (2H, tq, J = 7.4 Hz, 7.4 Hz), 0.89 (3H, t,J = 7.4 Hz). 117

(DMSO-d₆) δ 9.97 (1H, s), 7.34 (1H, s), 7.32- 7.28 (2H, m), 7.24-7.20(1H, m), 6.46 (2H, brs), 6.07 (1H, d, J = 5.1 Hz), 5.10 (1H, d, J = 5.1Hz), 4.84 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 3.57 (3H, s), 1.62 (2H, tt,J = 7.4 Hz, 6.6 Hz), 1.38 (2H, tq, J = 7.4 Hz, 7.4 Hz), 0.90 (3H, t, J =7.4 Hz). 118

(DMSO-d₆) δ 10.11 (1H, brs), 8.65 (1H, dd, J = 0.6, 5.0 Hz), 7.93 (1H,d, J = 0.9 Hz), 7.31 (1H, dd, J = 0.6, 5.0 Hz), 6.53 (2H, brs), 4.98(2H, s), 4.11 (2H, t, J = 6.8 Hz), 3.86 (3H, s), 1.58 (2H, 5, J = 6.6Hz), 1.33 (2H, 6, J = 7.3 Hz), 0.87 (3H, t, J = 7.3 Hz). 119

(DMSO-d₆) δ 10.11 (1H, brs), 7.65 (1H, d, J = 3.8 Hz), 7.14 (1H, d, J =3.8 Hz), 6.53 (2H, brs), 5.06 (2H, s), 4.16 (2H, t, J = 6.6 Hz), 3.78(3H, s), 1.63 (2H, 5, J = 6.6 Hz), 1.37 (2H, 6, J = 7.3 Hz), 0.90 (3H,t, J = 7.3 Hz). 120

(DMSO-d₆) δ 10.00 (1H, brs), 7.09 (2H, s), 7.05 (1H, s), 6.47 (2H, brs),4.81 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 3.63 (4H, s), 3.58 (6H, s), 1.62(2H, 5, J = 6.6 Hz), 1.37 (2H, 6, J = 7.3 Hz), 0.90 (3H, t, J = 7.3 Hz).121

(DMSO-d₆) δ 10.09 (1H, brs), 8.45 (1H, d, J = 2.0 Hz), 8.38 (1H, d, J =2.0Hz), 7.60 (1H, m), 6.50 (2H, brs), 4.88 (2H, s), 4.14 (2H, t, J = 6.6Hz), 3.73 (2H, s), 3.60 (3H, s), 1.62 (2H, 5, J = 6.6 Hz), 1.37 (2H, 6,J = 7.4 Hz), 0.90 (3H, t, J = 7.3 Hz).

TABLE 24 Comp. ex. Structure 1H-NMR 1

(DMSO-d₆) δ 612.99 (1H, (DMSO-d6) 512.99 (1H, brs), 10.03 (1H, s), 7.88(1H, s), 7.84 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 7.8 Hz), 7.45 (1H,t, J = 7.8 Hz), 6.48 (2H, brs), 4.91 (2H, s), 4.14 (2H, t, J = 6.5 Hz),1.60 (2H, 5, J = 7.0 Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.89 (3H, t, J = 7.3Hz). 3

(DMSO-d₆) δ 13.08 (1H, brs), 10.02 (1H, brs), 7.09 (1H, d, J = 2.4 Hz),6.45 (3H, m), 4.91 (2H, s), 4.13 (2H, t, J = 6.5 Hz), 1.64 (2H, 5, J =6.8 Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz). 5

(DMSO-d₆) δ 12.31 (1H, brs), 10.03 (1H, brs), 7.22 (4H, m), 6.47 (2H,brs), 4.83 (2H, s), 4.14 (2H, t, J = 6.8 Hz), 3.50 (2H, s), 1.60 (2H, 5,J = 6.8 Hz), 1.38 (2H, 6, J = 7.6 Hz), 0.90 (3H, t, J = 7.0 Hz). 6

(DMSO-d₆) δ 13.14 (1H, brs), 10.01 (1H, brs), 7.22 (4H, m), 6.49 (2H,brs), 4.83 (2H, s), 4.14 (2H, t, J = 6.5 Hz), 3.53 (2H, s), 1.62 (2H, 5,J = 6.8 Hz), 1.36 (2H, 6, J = 7.0 Hz), 0.90 (3H, t, J = 7.3 Hz). 8

(DMSO-d₆) δ 12.40 (1H, brs), 10.23 (1H, brs), 7.29 (5H, m), 6.50 (2H,s), 4.90 (2H, s), 3.53 (2H, s). 9

(DMSO-d₆) δ 9.68 (1H, s), 7.29 (5H, m), 6.06 (3H, brs), 4.80 (2H, s), N4.60 (1H, t, J = 4.4 Hz), 3.46 (2H, q, J = 4.4 Hz), 3.23 (2H, q, J = 4.4Hz). 10

(DMSO-d₆) δ 9.70 (1H, brs), 8.42 (1H, s), 7.59 (1H, d, J = 8.0 Hz), 7.20(1H, d, J = 8.0 Hz), 6.10 (1H, t, J = 6.0 Hz), 6.06 (2H, brs), 4.78 (2H,s), 4.62 (1H, t, J = 6.0 Hz), 3.50 (1H, q, J = 6.0 Hz), 3.25 (2H, q, J =6.0 Hz), 2.42 (3H, s). 11

(DMSO-d₆) δ 10.13 (1H, s), 8.43 (1H, d, J = 2.0 Hz), 7.60 (1H, dd, J =8.0, 2.0 Hz), 7.22 (1H, d, J = 8.0 Hz), 6.55 (2H, brs), 4.84 (2H, s),4.80 (1H, t, J = 4.8 Hz), 4.16 (2H, t, J = 4.8 Hz), 3.64 (2H, q, J = 4.8Hz), 2.42 (3H, s). 12

(DMSO-d₆) δ 10.44 (1H, brs), 7.34 (5H, m), 6.64 (2H, brs), 4.85 (2H, s),3.82 (2H, s). 13

(DMSO-d₆) δ 12.26 (br s, 1H), 8.16 (s, 1H), 7.39-7.17 (m, 5H), 5.29 (s,2H), 3.22 (t, 2H, J = 7.2 Hz), 2.66 (t, 2H, J = 6.9 Hz). 14

(DMSO-d₆) δ 9.70 (1H, s), 8.43 (1H, d, J = 2.0 Hz), 7.60 (1H, dd, J =8.0, 2.0 Hz), 7.20 (1H, d, J = 8.0 Hz), 6.11 (2H, brs), 6.02 (1H, t, J =5.7 Hz), 4.81 (1H, brs), 4.78 (2H, s), 4.56 (1H, t, J = 8.3 Hz), 3.57(1H, m), 3.33 (3H, m), 3.12 (1H, m), 2.42 (3H, s). 15

(DMSO-d₆) δ 12.04 (1H, brs), 10.20 (1H, brs), 7.26 (5H, m), 6.42 (2H,s), 4.88 (2H, s), 2.83 (2H, d, J = 7.2 Hz), 2.65 (2H, d, J = 7.2 Hz). 16

(DMSO-d₆)δ 12.80 (1H, brs), 10.00 (1H, brs), 7.28 (5H, m), 6.52 (2H, s),4.83 (2H, s), 4.70 (2H, s). 17

(DMSO-d₆) δ 10.57 (1H, brs), 8.70 (1H, s), 8.17 (1H, s), 7.68 (1H, d, J= 7.0 Hz), 6.83 (2H, brs), 5.04 (2H, s), 2.87 (2H, d, J = 7.1 Hz), 2.66(2H, d, J = 6.9 Hz), 2.61 (3H, s). 18

(DMSO-d₆) δ 10.76 (1H, brs), 7.28 (2H, d, J = 8.1Hz), 7.19 (2H, d, J =8.1Hz), 4.91 (2H, s), 3.52 (2H, s), 2.93 (2H, d, J = 7.1 Hz), 2.72 (2H,d, J = 6.9 Hz). 19

(DMSO-d₆) δ 12.50 (1H, brs), 9.97 (1H, brs), 6.46 (2H, brs), 6.19 (1H,d, J = 3.1 Hz), 6.16 (1H, d, J = 3.1 Hz), 4.79 (2H, s), 4. 14 (2H, t, J= 6.6 Hz), 3.59 (2H, s), 1.63 (2H, 5, J = 6.6 Hz), 1.38 (2H, 6, J = 7.4Hz), 0.90 (3H, t, J = 7.3 Hz). 20

(DMSO-d₆) δ 11.16 (1H, brs), 9.86 (1H, brs), 7.16 (1H, t, J = 7.6 Hz),7.13 (1H, s), 7.08 (1H, d, J = 7.5 Hz), 7.03 (1H, d, J = 7.5 Hz), 6.76(2H, brs), 4.79 (2H, s), 4.13 (2H, t, J = 6.6 Hz), 2.70 (2H, t, J = 7.7Hz), 2.15 (2H, t, J = 7.7 Hz), 1.62 (2H, 5, J = 6.6 Hz), 1.36 (2H, 6, J= 7.5 Hz), 0.89 (3H, t, J = 7.4 Hz). 21

(DMSO-d₆) δ 11.10 (1H, brs), 9.90 (1H, brs), 8.07 (1H, d, J = 2.2 Hz),7.42 (1H, dd, J = 2.4, 8.8 Hz), 6.74 (3H, m), 4.68 (2H, s), 4.15 (2H, t,J = 6.6 Hz), 4.04 (2H, m), 2.85 (2H, t, J = 10.8 Hz), 2.08 (1H, m), 1.73(2H, m), 1.64 (2H, 5, J = 6.6 Hz), 1.46 (2H, m), 1.38 (2H, 6, J = 7.3Hz), 0.92 (3H, t, J = 7.3 Hz). 22

(DMSO-d₆) δ 11.51 (1H, brs), 8.06 (1H, d, J = 2.3 Hz), 7.43 (1H, dd, J =2.4, 8.8 Hz), 6.87 (2H, s), 6.79 (1H, d, J = 8.8 Hz), 4.67 (2H, s), 4.14(4H, m), 2.75 (3H, m), 1.93 (2H, m), 1.50 (6H, m), 0.92 (3H, t, J = 7.3Hz). 23

(DMSO-d₆) δ 13.14 (2H, 7.64 (1H, d, J = 7.9 Hz), 7.59 (1H, d, J = 1.5Hz), 7.45 (1H, dd, J = 1,7, 7.9 Hz), 6.48 (2H, brs), 4.93 (2H, s), 4.13(2H, t, J = 6.6 Hz), 1.61 (2H, 5, J = 6.6 Hz), 1.35 (2H, 6, J = 7.3 Hz),0.89 (3H, t, J = 7.4 Hz). 24

(DMSO-d₆) δ 13.31 (1H, brs), 10.08 (1H, brs), 8.36 (1H, s), 8.11 (2H,s), 6.52 (2H, brs), 4.98 (2H, s), 4.15 (2H, t, J = 6.6 Hz), 1.61 (2H, 5,J = 6.7 Hz), 1.35 (2H, 6, J = 7.3 Hz), 0.89 (3H, t, J = 7.4 Hz). 25

(DMSO-d₆) δ 12.44 (1H, brs), 9.98 (1H, brs), 8.46 (1H, d, J = 1.9 Hz),7.65 (1H, dd, J = 2.3, 8.0 Hz), 7.29 (1H, d, J = 7.8 Hz), 6.46 (2H,brs), 4.87 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 3.43 (2H, s), 1.62 (2H, 5,J = 7.7 Hz), 1.37 (2H, 6, J = 7.6 Hz), 0.91 (3H, t, J = 7.4 Hz). 26

(DMSO-d₆) δ 10.65 (1H, brs), 8.32 (1H, s), 7.60 (1H, d, J = 7.1 Hz),7.34 (1H, d, J = 8.3 Hz), 6.66 (2H, brs), 5.70 (1H, brs), 4.78 (2H, s),4.15 (4H, m), 3.51 (1H, t, J = 8.7 Hz), 3.14 (1H, m), 1.90 (2H, m), 1.63(2H, 5, J = 7.0 Hz), 1.37 (2H, 6, J = 7.5 Hz), 0.91 (3H, t, J = 7.3 Hz).27

(DMSO-d₆) δ 12.32 (1H, brs), 9.97 (1H, s), 7.26 (1H, dd, J = 7.6 Hz, 7.6Hz), 7.20 (1H, s), 7.17-7.14 (2H, m), 6.47 (2H, brs), 4.83 (2H, s), 4.26(2H, t, J = 4.8 Hz), 3.58 (2H, t, J = 4.8 Hz), 3.53 (2H, s), 3.26 (3H,s). 28

(DMSO-d₆) δ 12.29 (1H, brs), 9.98 (1H, brs), 7.26 (1H, dd, J = 7.6 Hz,7.6 Hz), 7.21 (1H, s), 7.18-7.15 (2H, m), 6.74 (2H, brs), 4.81 (2H, s),3.69 (2H, s), 3.40-3.17 (2H, m), 1.48 (2H, tt, J = 7.2 Hz, 7.2 Hz), 1.30(2H, tq, J = 7.2 Hz, 7.2 Hz), 0.88 (3H, t, J = 7.2 Hz). 29

(DMSO-d₆) δ 12.39 (1H, brs), 10.39 (1H, brs), 7.27-7.25 (1H, m), 7.17(1H, s), 7.17-7.11 (2H, m), 6.91 (2H, brs), 4.92 (2H, s), 3.53 (2H, s).30

(DMSO-d₆) δ 12.29 (1H, brs), 10.11 (1H, s), 7.28 (1H, dd, J = 7.6 Hz,7.6 Hz), 7.23 (1H, s), 7.19 (1H, d, J = 7.6 Hz), 7.15 (1H, d, J = 7.6Hz), 6.52 (2H, brs), 4.90 (1H, brs), 4.85 (2H, s), 3.60 (2H, t, J = 6.8Hz), 3.54 (2H, s), 3.12 (2H, t, J = 6.8 Hz). 31

(DMSO-d₆) δ 12.27 (1H, brs), 9.95 (1H, brs), 7.26-7. 19 (4H, m), 6.43(2H, brs), 4.81 (2H, s), 4.13 (2H, t, J = 6.6 Hz), 3.62 (1H, q, J = 6.9Hz), 1.61 (2H, 5, J = 6.9 Hz), 1.36 (2H, 6, J = 7.0 Hz), 1.30 (3H, d, J= 6.9 Hz), 0.89 (3H, t, J = 7.3 Hz). 32

(DMSO-d₆) δ 12.32 (1H, brs), 9.94 (1H, brs), 7.37-7. 10 (4H, m), 6.43(2H, brs), 4.83 (2H, s), 4.14 (2H, t, J = 6.6 Hz), 1.62 (2H, 5, J = 6.9Hz), 1.42 (6H, s), 1.36 (2H, 6, J = 7.0 Hz), 0.89 (3H, t, J = 7.3 Hz).33

(DMSO-d₆) δ 9.84 (1H, brs), 7.80 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J =8.1 Hz), 6.39 (2H, brs), 4.10 (2H, t, J = 6.6 Hz), 3.93 (2H, t, J = 6.9Hz), 3.05 (2H, t, J = 7.3 Hz), 1.61 (2H, 5, J = 7.0 Hz), 1.37 (2H, 6, J= 7.4 Hz), 0.91 (3H, t, J = 7.3 Hz). 34

(DMSO-d₆) δ 10.16 (1H, brs), 8.01 (1H, s), 7.77 (1H, d, J = 7.8 Hz),7.59 (1H, d, J = 7.8 Hz), 7.27 (6H, m), 6.60 (2H, brs), 4.91 (2H, s),4.35 (2H, s). 35

(DMSO-d₆) δ 10.18 (1H, brs), 7.76 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J =8.2 Hz) 7.28 (5H, m), 6.62 (2H, brs), 4.91 (2H, s), 4.34 (2H, s). 36

(DMSO-d₆) δ 12.32 (1H, brs), 10.16 (1H, brs), 7.33-7.09 (9H, m), 6.59(2H, brs), 4.91 (2H, s), 4.28 (2H, s), 3.49 (2H, s). 37

(DMSO-d₆) δ12.30 (1H, brs), 10.13 (1H, brs), 7.28 (7H, m), 7.09 (2H, d,J = 8.0 Hz), 6.58 (2H, brs), 4.91 (2H, s), 4.27 (2H, s), 3.50 (2H, s).

The preferable compounds of the present invention are illustrated below.

TABLE 25

No. —R⁹ 201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

TABLE 26

No. —Y¹—Q¹ X —R⁹ 331 —Bu —

332 —CH₂OH —

333 —(CH₂)₂OH —

334 —(CH)₂OMe —

335 —Bu —

336 —CH₂OH —

337 —(CH₂)₂OH —

338 —(CH₂)₂OH —

339 —(CH)₂OMe —

340 —Bu —

341 —CH₂OH —

342 —(CH₂)₂OH —

343 —CH₂OMe —

344 —Bu —

345 —CH₂OH —

346 —(CH₂)₂OH —

347 —(CH)₂OMe —

348 —Bu —

349 —CH₂OH —

350 —(CH₂)₂OH —

351 —(CH)₂OMe —

352 —Bu —

353 —CH₂OH —

354 —(CH₂)₂OH —

355 —CH₂OMe —

356 —Bu —

357 —CH₂OH —

358 —(CH₂)₂OH —

359 —(CH₂)OMe NH

360 —Bu NH

361 —(CH₂)₃OH NMe

362 —(CH)₂OH NH

363 —(CH₂)₃OEt NH

364 —(CH₂)OMe NMe

365 —Bu NH

366 —(CH₂)₃OH NH

367 —CH₂OH NH

368 —(CH₂)₃OEt NMe

369 —CH₂OMe NH

370 —Bu NH

371 —(CH₂)₃OH NMe

372 —CH₂OH NH

373 —(CH₂)₃OEt NH

374 —CH₂OMe NH

375 —Bu NMe

376 —(CH₂)₃OH NH

377 —CH₂OH NH

378 —(CH₂)₃OEt NMe

379 —CH₂OMe NH

380 —Bu NH

381 —(CH₂)₃OH NH

382 —(CH)₂H NMe

383 —(CH₂)₃OEt NH

384 —CH₂OMe NH

385 —Bu NMe

386 —(CH₂)₃OH NH

387 —CH₂OH NH

388 —(CH₂)₃OEt NH

389 —CH₂OMe NMe

390 —Bu NH

391 —(CH₂)₂OH NH

392 —(CH₂)₂OMe NMe

393 —Bu NH

394 —(CH₂)₂OH NH

395 —(CH₂)2OMe NH

396 —Bu NMe

397 —(CH₂)₂OH NH

398 —(CH₂)₂OMe NH

399 —Bu NMe

400 —(CH₂)₂OH NH

401 —(CH₂)₂OMe NH

402 —Bu NH

403 —(CH₂)₂OH NMe

404 —Bu S

405 —(CH₂)₃OH S

406 —CH₂OH S

407 —(CH₂)₃OEt S

408 —CH₂OMe S

409 —Bu S

410 —(CH₂)₃OH S

411 —CH₂OH S

412 —(CH₂)₃OEt S

413 —CH₂OMe S

414 —Bu S

415 —(CH₂)₃OH S

416 —CH₂OH S

417 —(CH₂)₃OH S

418 —(CH)₂OH S

419 —(CH₂)₃OEt S

420 —CH₂OMe S

421 —Bu S

422 —(CH₂)₃OH S

423 —CH₂OH S

424 —(CH₂)₃OEt S

425 —CH₂OMe S

426 —Bu S

427 —(CH₂)₃OH S

428 —CH₂OH S

429 —(CH₂)₃OEt S

430 —CH₂OMe S

431 —Bu S

432 —(CH₂)₃OH S

433 —CH₂OH S

434 —(CH₂)₃OEt S

435 —CH₂OMe S

436 —Bu S

437 —(CH₂)₂H S

438 —(CH₂)₂OMe S

439 —Bu S

440 —(CH₂)₂OH S

441 —(CH₂)₂OMe S

442 —Bu S

443 —(CH₂)₂OH S

444 —(CH₂)₂OMe S

445 —Bu S

446 —(CH₂)₂OH S

447 —(CH₂)₂OMe S

448 —CH₂OH O

449 —(CH₂)₃OEt O

450 —(CH₂)₃OH O

451 —CH₂OMe O

452 —CH₂OH O

453 —(CH₂)₃OEt O

454 —(CH₂)₃OH O

455 —CH₂OMe O

456 —CH₂OH O

457 —(CH₂)₃OEt O

458 —(CH₂)₃OH O

459 —CH₂OMe O

460 —CH₂OH O

461 —(CH₂)₃OEt O

462 —(CH₂)₃OH O

463 —CH₂OMe O

464 —CH₂OH O

465 —(CH₂)₃OEt O

466 —(CH₂)₃OH O

467 —CH₂OMe O

468 —CH₂OH O

469 —(CH₂)₃OEt O

470 —(CH₂)₃OH O

471 —CH₂OMe O

472 —CH₂OH O

473 —(CH₂)₃OEt O

474 —(CH₂)₂OH O

475 —(CH₂)₂OMe O

476 —(CH₂)₂OH O

477 —(CH₂)₂OMe O

478 —(CH₂)₂OH O

479 —(CH₂)₂OMe O

480 —(CH₂)₂OH O

481 —(CH₂)₂OMe O

482 —(CH₂)₂OH O

483 —(CH₂)₂OMe O

TABLE 27

No. —Y1—Q1 X 484 —CO₂Me — 485 —CO₂CH₂CH═CH₂ — 486 —CO₂CH₂CF₃ — 487—CO₂(CH₂)₂OMe — 488 —CO₂(CH₂)₂OH — 489 —CO₂(CH₂)NMe₂ — 490 —CO₂Bn — 491

— 492

— 493 —CH₂CO₂CH₂Cl — 494 —CH₂CO₂(CH₂)₃OEt — 495 —CH₂CO₂(CH₂)₄OH — 496

— 497

— 498

— 499 —(CH₂)₂CO2Bn — 500 —(CH₂)₃CO₂CH₂C1 — 501 —(CH₂)₄CO₂(CH₂)₃OEt — 502—(CH₂)₂CO₂(CH₂)₂OH — 503

— 504

— 505

— 506 —COS—^(i)Pr — 507 —COS(CH₂)₂OH — 508 —CH₂COS(CH₂)₂OMe — 509

— 510 —CH₂OCO₂Et — 511 —(CH₂)₃OCO₂(CH₂)₂OMe — 512 —CH₂OCOEt — 513—(CH₂)₂OCOBn — 514

— 515 —CONMe₂ — 516 —CH₂CONH(CH₂)NMe₂ — 517

— 518 —(CH₂)₃CONH(CH₂)OMe — 519 —CH₂OCONMe₂ — 520

— 521

— 522

NH 523 —CH₂CO₂CH₂CF₃ NMe 524 —CH₂CO₂(CH₂)₃OEt NEt 525 —CH₂CO₂(CH₂)₄OH NH526

NMe 527

NEt 528

NH 529 —(CH₂)₂CO₂Bn NMe 530 —(CH₂)₃CO₂CH₂Cl NEt 531 —(CH₂)₄CO₂(CH₂)₃OEtNH 532 —(CH₂)₂CO₂(CH₂)₂OH NMe 533

NEt 534

NH 535

NMe 536 —CH₂COSBu NEt 537 —CH₂COS(CH₂)₂OH NH 538 —CH₂COS(CH₂)₂OMe NMe539 —(CH₂)₂COS(CH₂)₂NMeEt NEt 540 —CH₂OCO₂Et NH 541 —(CH₂)₃OCO₂(CH₂)₂OMeNMe 542 —CH₂OCOEt NEt 543 —(CH₂)₂OCOBn NH 544

NMe 545 —CH₂CONMe₂ NEt 546 —CH₂CONH(CH₂)NMe₂ NH 547

NMe 548 —(CH₂)₃CONH(CH₂)OMe NEt 549 —CH₂OCONMe₂ NH 550

NMe 551

NEt 552

S 553 —CH₂CO₂CH₂CF₃ S 554 —CH₂CO₂(CH₂)₄OH S 555

S 556

S 557 —(CH₂)₂CO₂Bn S 558 —(CH₂)₄CO₂(CH₂)₃OEt S 559

S 560

S 561 —CH₂COSBu S 562 —CH₂COS(CH₂)₂OMe S 563 —(CH₂)₂COS(CH₂)₂NMeEt S 564—(CH₂)₃OCO₂(CH₂)₂OMe S 565 —CH₂OCOEt S 566

S 567 —CH₂CONMe₂ S 568

S 569 —(CH₂)₃CONH(CH₂)OMe S 570

S 571

S 572

O 573 —CH₂CO₂(CH₂)₃OEt O 574 —CH₂CO₂(CH₂)₄OH O 575

O 576

O 577 —(CH₂)₃CO₂CH₂Cl O 578 —(CH₂)₄CO₂(CH₂)₃OEt O 579

O 580

O 581 —CH₂COSBu O 582 —CH₂COS(CH₂)₂OH O 583 —(CH₂)₂COS(CH₂)₂NMeEt O 584—CH₂OCO₂Et O 585 —CH₂OCOEt O 586 —(CH₂)₂OCOBn O 87 —CH₂CONMe₂ O 588—CH₂CONH(CH₂)NMe₂ O 589 —(CH₂)₃CONH(CH₂)OMe O 590 —CH₂OCONMe₂ O 591

O

TABLE 28

No. —Y¹—Q¹ X —R⁹ 592 —CO₂Me —

593 —CO₂CH₂CF₃ —

594 —CO₂(CH₂)₂OH —

595 —CO₂Bn —

596

—

597 —CH₂CO₂(CH₂)₃OEt —

598

—

599

—

600 —(CH₂)₃CO₂CH₂Cl —

601 —(CH₂)₂CO₂(CH₂)₂OH —

602

—

603 —COS—^(i)Pr —

604 —CH₂COS(CH₂)₂OMe —

605 —CH₂OCO₂Et —

606 —CH₂OCOEt —

607

—

608 —CH₂CONH(CH₂)NMe₂ —

609 —(CH₂)₃CONH(CH₂)OMe —

610

—

611 —CH₂CO₂CH₂CF₃ NMe

612 —CH₂CO₂(CH₂)₄OH NH

613

NEt

614 —(CH₂)₂CO₂Bn NMe

615 —(CH₂)₄CO₂(CH₂)₃OEt NH

616

NEt

617

NMe

618 —CH₂COS(CH₂)₂OH NH

619 —(CH₂)₂COS(CH₂)₂NMeEt NEt

620 —(CH₂)₃OCO₂(CH₂)₂OMe NMe

621 —(CH₂)₂OCOBn NH

622 —CH₂CONMe₂ NEt

623

NMe

624 —CH₂OCONMe₂ NH

625

NEt

626

S

627 —CH₂CO₂(CH₂)₄OH S

628

S

629 —(CH₂)₄CO₂(CH₂)₃OEt S

630

S

631 —CH₂COS(CH₂)₂OMe S

632 —(CH₂)₃OCO₂(CH₂)₂OMe S

633

S

634

S

635

S

636 —CH₂CO₂(CH₂)₃OEt O

637

O

638 —(CH₂)₃CO₂CH₂Cl O

639

O

640 —CH₂COSBu O

641 —(CH₂)₂COS(CH₂)₂NMeEt O

642 —CH₂OCOEt O

643 —CH₂CONMe₂ O

644 —(CH₂)₃CONH(CH₂)OMe O

645

O

646 —CO₂Me —

647 —CO₂CH₂CH═CH₂ —

648 —CO₂(CH₂)₂OMe —

649 —CO₂(CH₂)₂OH —

650 —CO₂Bn —

651

—

652 —CH₂CO₂CH₂Cl —

653 —CH₂CO₂(CH₂)₃OEt —

654

—

655

—

656 —(CH₂)₂CO₂Bn —

657 —(CH₂)₃CO₂CH₂Cl —

658 —(CH₂)₂CO₂(CH₂)₂OH —

659

—

660

—

661 —COS—^(i)Pr —

662 —CH₂COS(CH₂)₂OMe —

663 —(CH₂)₂COS(CH₂)₂NMeEt —

664 —(CH₂)₃OCO₂(CH₂)₂OMe —

665 —(CH₂)₂OCOBn —

666

—

667 —CH₂CONH(CH₂)NMe₂ —

668

—

669 —CH₂OCONMe₂ —

670

—

671 —CH₂CO₂CH₂CF₃ NMe

672 —CH₂CO₂(CH₂)₄OH NH

673

NEt

674 —(CH₂)₂CO₂Bn NMe

675 —(CH₂)₄CO₂(CH₂)₃OEt NH

676

NEt

677

NMe

678 —CH₂COS(CH₂)₂OH NH

679 —(CH₂)₂COS(CH₂)₂NMeEt NEt

680 —(CH₂)₃OCO₂(CH₂)₂Me NMe

681 —(CH₂)₂OCOBn NH

682 —CH₂CONMe₂ NEt

683

NMe

684 —CH₂OCONMe₂ NH

685

NEt

686

S

687 —CH₂CO₂Me S

688

S

689 —(CH₂)₄CO₂(CH₂)₃OEt S

690

S

691 —CH₂COS(CH₂)₂OMe S

692 —(CH₂)₃OCO₂(CH₂)₂OMe S

693

S

694

S

695

S

696

O

697 —CH₂CO₂(CH₂)₄OH O

698

O

699 —(CH₂)₄CO₂Et O

700

O

701 —CH₂COS(CH₂)₂OH O

702 —CH₂OCO₂Et O

703 —(CH₂)₂OCOMe O

704 —CH₂CONH(CH₂)NMe₂ O

705 —CH₂OCONMe₂ O

706 —CO₂(CH₂)₂OMe —

707 —(CH₂)₂CO₂Et —

708

—

709 —CH₂COSMe —

710 —CH₂OAc —

711 —CH₂OCO₂Me —

712 —CH₂CO₂Me —

713 —CH₂CO₂(CH₂)₂NMe₂ —

714 —(CH₂)₂CO₂Bn —

715

—

716

—

717

—

718 —CH₂CHMeCO₂Me —

719

—

720

—

721 —CO₂(CH₂)₂OMe —

722 —(CH₂)₂CO₂Et —

723

—

724 —CH₂CONMe₂ —

725 —CH₂OCO(CH₂)₂OH —

726 —CH₂OCONMe₂ —

727 —(CH₂)₂CO2Bn —

728

—

729

—

730

—

731 —CH₂CHMeCO₂Me —

732

—

733

—

734 —COS(CH₂)₂OMe —

735 —CO₂(CH₂)₂OH —

736 —CHMeCO₂CH₂CF₃ —

737

—

738 —CH₂COSMe —

739 —CH₂OAc —

740 —CH₂OCO₂Et —

741 —(CH₂)₂CO₂Bn —

742

—

743

—

744

—

745 —CH₂CHMeCO₂Me —

746

—

747 —(CH₂)₂OCO₂CH₂CF₃ —

748 —CH₂CONMe(CH₂)₂OH —

749 —CO₂(CH₂)₂OMe —

750 —(CH₂)₂CO₂Et —

751

—

752 —CH₂COSMe —

753 —CH₂OAc —

754 —CH₂OCO₂Me —

755

—

756

—

757 —CH₂CHMeCO₂Me —

758

—

759 —(CH₂)₂OCO₂CH₂CF₃ —

760 —CH₂OCO(CH₂)₂OMe —

761 —CH₂OCONMe₂ —

762 —(CH₂)₂CO₂Bn —

763

—

764 —CH₂CO₂(CH₂)₂NMe₂ —

765 —(CH₂)₂CO₂Bn —

766

—

767 —CH₂COSMe —

768 —CH₂OCO₂Et —

769 —CHMeCO₂CH₂CF₃ —

770 —CO₂(CH₂)₂OMe —

771

—

772 —CH₂OAc —

773

—

774 —CH₂CHMeCO₂Me —

775 —(CH₂)₂OCO₂CH₂CF₃ —

776 —CH₂OCONMe₂ —

777

—

778 —(CH₂)₂CO₂Bn —

779 —CO₂(CH₂)₂OMe —

780

—

781 —CH₂OCO(CH₂)₂OH —

782 —CO₂(CH₂)₂OMe —

783

—

784 —CH₂OCO(CH₂)₂OEt —

785 —(CH₂)₂CO₂Bn —

786 —CH₂CO₂(CH₂)₂OMe NH

787

NEt

788 —(CH₂)₂OAc NMe

789 —CH₂CO₂Me NH

790 —(CH₂)₂CO₂Bn NEt

791

NMe

792 —CH₂CHMeCO₂Me NH

793

NEt

794 —CH₂CO₂(CH₂)₂OMe NH

795

NEt

796 —(CH₂)₃OCO(CH₂)₂OH NMe

797 —(CH₂)₂CO₂Bn NH

798

NEt

799 —CH₂CHMeCO₂Me NMe

800

NMe

801 —CH₂CO₂(CH₂)₂OH NH

802

NEt

803 —(CH₂)2OCOPr NMe

804 —(CH₂)₂CO₂Bn NH

805

NEt

806 —CH₂CHMeCO₂Me NMe

807 —(CH₂)₂OCO₂CH₂CF₃ NMe

808 —CH₂CO₂Me NH

809

NEt

810 —(CH₂)₄OAc NMe

811

NH

812 —CH₂CHMeCO₂Me NEt

813 —(CH₂)₂OCO₂CH₂CF₃ NMe

814 —(CH₂)₃OCONMe₂ NH

815

NEt

816 —(CH₂)₂CO₂Bn NMe

817 —CH₂COSMe NH

818 —CHMeCO₂CH₂CF₃ NEt

819

NMe

820

NH

821 —(CH₂)₂OCO₂CH₂CF₃ NEt

822

NMe

823 —CH₂CO₂Bu NH

824 —(CH₂)₂OCO(CH₂)₂OH NEt

825

NH

826 —(CH₂)₂CO₂Bn NEt

827 —CH₂CO₂iPr S

828 —(CH₂)₂CO₂Et S

829 —CH₂COSMe S

830 —(CH₂)₂OCOEt S

831 -CH₂CO₂Me S

832 —CH₂CO₂(CH₂)₂NMe₂ S

833

S

834

S

835 —CH₂CHMeCO₂Me S

836

S

837 —CH₂CO₂(CH₂)₂OMe S

838 —(CH₂)₂CO₂Et S

839 —CH₂CONMe₂ S

840 —CH₂OCO(CH₂)₂OH S

841 —(CH₂)₂CO₂Bn S

842

S

843

S

844 —CH₂CHMeCO₂Me S

845

S

846 —CH₂COS(CH₂)₂NMe₂ S

847 —(CH₂)₄CO₂Me S

848 —CHMeCO₂CH₂CF₃ S

849 —CH₂COSMe S

850 —(CH₂)₃OAc S

851 —(CH₂)₂CO₂Bn S

852

S

853

S

854 —CH₂CHMeCO₂Me S

855 —(CH₂)₄OCO₂CH₂CF₃ S

856 —CH₂CONMe(CH₂)₂OH S

857 —CH₂CO₂(CH₂)₂OMe S

858 —(CH₂)₃CO₂Et S

859 —CH₂COSMe S

860 —(CH₂)₂OCO(CH₂)₂OMe S

861

S

862

S

863

S

864 —(CH₂)₂OCO₂CH₂CF₃ S

865 —(CH₂)₂OCONMe₂ S

866 —(CH₂)₂CO₂Bn S

867 —CH₂CO₂(CH₂)₂NMeEt S

868 —(CH₂)₂CO₂Bn S

869 —CH₂COSMe S

870 —(CH₂)₃OCO₂Et S

871 —CHMeCH₂CO₂(CH₂)₂OMe S

872

S

873

S

874 —CH₂CHMeCO₂Me S

875 —(CH₂)₂OCONMe₂ S

876

S

877 —CH₂CO₂(CH₂)₂OMe S

878

S

879 —CH₂CO₂(CH₂)₂NMe₂ S

880

S

881 —(CH₂)₂CO₂Bn S

882 —(CH₂)₂CO₂Et O

883 —CH₂COSMe O

884 —(CH₂)₂OCO₂Me O

885 —CH₂CO₂(CH₂)₂NMe₂ O

886

O

887

O

888

O

889 —(CH₂)₂CO₂Et O

890 —CH₂CONMe₂ O

891 —(CH₂)₂OCONMe₂ O

892

O

893

O

894

O

895 —CH₂COS(CH₂)₂OMe O

896 —CHMeCO₂CH₂CF₃ O

897 —CH₂COSMe O

898 —(CH₂)₅OCO₂Et O

899

O

900

O

901

O

902 —CH₂CONMe(CH₂)₂OH O

903 —CH₂CO₂Bu O

904

O

905 —(CH₂)₃OAc O

906

O

907 —CH₂CHMeCO₂Me O

908 —(CH₂)₂OCO₂CH₂CF₃ O

909 —(CH₂)₂OCONMe₂ O

910

O

911 —(CH₂)₂CO₂Bn O

912 —CH₂COSMe O

913 —CHMeCO₂CH₂CF₃ O

914

O

915

O

916 —(CH₂)₂OCO₂CH₂CF₃ O

917

O

918 —(CH₂)₃CO₂(CH₂)₂OMe O

919 —(CH₂)₂OCO(CH₂)₂OH O

920

O

921 —(CH₂)₂CO₂Bn O

INDUSTRIAL APPLICABILITY

The present invention provides an adenine compound useful as amedicament for the topical administration which is characterized inshowing the medical effect by the topical administration and showingnone of the systemically pharmacological activity. The therapy andprevention for allergic diseases such as asthma and atopic dermatitis,viral diseases such as herpes, etc. becomes possible.

The invention claimed is:
 1. An adenine compound represented by ageneral formula (1):

wherein Ring A is benzene or naphthalene, n is an integer selected from0 to 2, m is an integer selected from 1 or 2, R is halogen atom,substituted or unsubstituted alkyl group, substituted or unsubstitutedcycloalkyl group, substituted or unsubstituted alkoxy group, orsubstituted or unsubstituted amino group, and when n is 2, R(s) may bethe same or different, X¹ is oxygen atom, sulfur atom, NR¹ (wherein RIis hydrogen atom or alkyl group) or a single bond, Y¹ is a single bond,or alkylene which may be substituted by oxo group, Y² is alkylene oroxyalkylene, Z is alkylene, Q¹ is hydrogen atom, halogen atom, hydroxygroup, alkoxy group, or a group selected from the group consisting ofSubstituents set forth below, Q² is a group selected from the groupconsisting of Substituents set forth below, Substituents: —COOR¹⁰;—COSR¹⁰ wherein R¹⁰ is substituted or unsubstituted alkyl group,substituted or unsubstituted cycloalkyl group, substituted orunsubstituted alkenyl group, substituted or unsubstituted cycloalkenylgroup, or substituted or unsubstituted alkynyl group, and when m is 2,(Y²-Q²)(s) may be the same or different, its tautomer or itspharmaceutically acceptable salt.
 2. The adenine compound, its tautomeror its pharmaceutically acceptable salt according to claim 1, wherein inthe general formula (1), the substituent(s), by which alkyl group,alkenyl group or alkynyl group in R¹⁰ is substituted, are the same ordifferent and at least one substituent selected from the groupconsisting of halogen atom, hydroxy group, substituted or unsubstitutedalkoxy group, substituted or unsubstituted amino group, substituted orunsubstituted aryl group, and substituted or unsubstituted heterocyclicgroup.
 3. The adenine compound, its tautomer or its pharmaceuticallyacceptable salt according to claim 1, wherein in the general formula(1), Z is methylene and Ring A is benzene.
 4. The adenine compound, itstautomer or its pharmaceutically acceptable salt according to claim 1,wherein in the general formula (1), Z is methylene, Ring A is benzene,R¹⁰ is alkyl group optionally substituted by hydroxy group, amino group,alkylamino group or dialkylamino group, and m is
 1. 5. The adeninecompound, its tautomer or its pharmaceutically acceptable salt accordingto claim 1; wherein in the general formula (1), Y¹ is C₁₋₅ alkylene, Q¹is hydrogen atom, hydroxy group or alkoxy group, Y² is C₁₋₃ alkylene, Q²is —COOR¹⁰, and m is
 1. 6. The adenine compound, its tautomer or itspharmaceutically acceptable salt according to claim 1, wherein in thegeneral formula (1), X¹ is oxygen atom, sulfur atom or NR¹ (wherein R¹is hydrogen atom or alkyl group).
 7. The adenine compound, its tautomeror its pharmaceutically acceptable salt according to claim 1, wherein inthe general formula (1), either 1) or 2) below obtains: 1) n is 0; 2) nis 1 or 2, and R is alkyl group, alkoxy group or halogen atom.
 8. Anadenine compound represented by a general formula (1):

wherein Ring A is benzene, n is an integer selected from 0 to 2, m is 1,R is halogen atom, substituted or unsubstituted alkyl group, substitutedor unsubstituted cycloalkyl group, substituted or unsubstituted alkoxygroup, or substituted or unsubstituted amino group, and when n is 2,R(s) may be the same or different, X¹ is oxygen atom, sulfur atom, NR¹(wherein R¹ is hydrogen atom or alkyl group) or a single bond, Y¹ isC₁₋₅ alkylene, Y² is a single bond, Z is methylene, Q¹ is hydrogen atom,hydroxy group or alkoxy group, Q² is —COOR²³ (wherein R²³ is alkyl groupsubstituted by amino group, alkylamino group or dialkylamino group), andm is 1, its tautomer or its pharmaceutically acceptable.
 9. The adeninecompound or its pharmaceutically acceptable salt according to claim 8,wherein in the general formula (1), X¹ is oxygen atom, sulfur atom orNR¹ (wherein R¹ is hydrogen atom or alkyl group).
 10. A compoundselected from the group consisting of2-Butoxy-8-hydroxy-9-{(6-ethoxycarbonylmethoxy-2-naphthyl)methyl}adenine),2-Butoxy-8-hydroxy-9-{4-(S-methylthiocarbonyl)methylbenzyl}adenine,2-Butoxy-9-{4-(S-ethylthiocarbonyl)methylbenzyl}-8-hydroxyadenine,2-Butoxy-8-hydroxy-9-{(6-methoxycarbonylmethoxy-2-naphthyl)methyl}adenine,2-Butoxy-8-hydroxy-9-{3-(2-hydroxyethoxycarbonyl)benzyl}adenine,2-Butoxy-8-hydroxy-9-{3-(2-dimethylaminoethoxycarbonyl)benzyl}adenine,2-Butoxy-8-hydroxy-9-{3-(2-morpholinoethoxycarbonyl)benzyl}adenine,2-Butoxy-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine,2-Butoxy-8-hydroxy-9-(4-methoxycarbonylmethylbenzyl)adenine,2-Butoxy-8-hydroxy-9-(4-isopropoxycarbonylmethylbenzyl)adenine,2-Butoxy-8-hydroxy-9-(4-methoxycarbonylmethoxybenzyl)adenine,2-Butoxy-8-hydroxy-9-{3-bromo-4-(methoxycarbonylmethoxy)benzyl}adenine,8-Hydroxy-2-(2-methoxycarbonylethyl)-9-(4-methoxycarbonylmethylbenzyl)adenine,2-Butoxy-8-hydroxy-9-(4-ethoxycarbonylmethylbenzyl)adenine,2-Butoxy-8-hydroxy-9-{3-(2,2,2-trifluoroethoxycarbonyl)methylbenzyl}adenine,2-Butoxy-8-hydroxy-9-{3-(2-fluoroethoxycarbonyl)methylbenzyl}adenine,2-Butoxy-8-hydroxy-9-{4-(2-hydroxyethoxycarbonyl)methylbenzyl}adenine,2-Butoxy-8-hydroxy-9-{4-(2-dimethylaminoethoxycarbonyl)methylbenzyl}adeninehydrochloride,2-Butoxy-8-hydroxy-9-{4-(2-morpholinoethoxycarbonyl)methylbenzyl}adenine,2-Butoxy-9-(3-ethoxycarbonylmethylbenzyl)-8-hydroxyadenine,2-Butoxy-8-hydroxy-9-(3-methoxycarbonylethylbenzyl)adenine,2-Butoxy-8-hydroxy-9-(4-methoxycarbonylethylbenzyl)adenine,2-Butoxy-9-(4-ethoxycarbonylethylbenzyl)-8-hydroxyadenine,2-Butoxy-9-{4-(1-hydroxy-3-methoxycarbonylpropoxy)benzyl}-8-hydroxyadenine,8-Hydroxy-9-(3-methoxycarbonylmethylbenzyl)-2-(2-methoxyethoxy)adenine,2-Butylamino-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine,2-Chloro-8-hydroxy-9-(3-methoxycarbonylmethylbenzyl)adenine,8-Hydroxy-2-(2-hydroxyethylthio)-9-(3-methoxycarbonylmethylbenzyl)adenine,2-Butoxy-8-hydroxy-9-[4-(1-methoxycarbonylethyl)benzyl]adenine,2-Butoxy-8-hydroxy-9-[3-(2-methoxycarbonyl-2-propyl)benzyl]adenine,2-Butoxy-8-hydroxy-9-(4-methoxycarbonylphenylethyl)adenine,2-Butoxy-8-hydroxy-9-[(2-methoxycarbonylmethyl)benzyl]adenine,2-Butoxy-8-hydroxy-9-[4-(2-methoxycarbonyl-2-methylethyl)benzyl]adenine,2-Butoxy-8-hydroxy-9-[3-((2R,S)-methoxycarbonylethyl)benzyl]adenine, and9-{3,5-Bis (methoxycarbonylmethyl)benzyl}-2-butoxy-8-hydroxyadenine. 11.A pharmaceutical composition comprising the compound of claim 1 or itspharmaceutically acceptable salt and a carrier.
 12. A method fortreatment of asthma or atopic dermatitis comprising administering to apatient in need thereof an effective amount of the compound of claim 1or its pharmaceutically acceptable salt as an active ingredient.